bims-lysosi Biomed News
on Lysosomes and signaling
Issue of 2021–07–25
thirty-one papers selected by
Stephanie Fernandes, Max Planck Institute for Biology of Ageing
  1. ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability.
  2. α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.
  3. A  conserved ubiquitin- and ESCRT-dependent pathway internalizes human lysosomal membrane proteins for degradation.
  4. Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.
  5. The mTOR-Autophagy Axis and the Control of Metabolism.
  6. VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.
  7. SAR1B senses leucine levels to regulate mTORC1 signalling.
  8. Tsc1 regulates tight junction independent of mTORC1.
  9. Delivering progranulin to neuronal lysosomes protects against excitotoxicity.
  10. CLN3, at the crossroads of endocytic trafficking.
  11. How the amino acid leucine activates the key cell-growth regulator mTOR.
  12. mTORC1 Signaling Regulates Proinflammatory Macrophage Function and Metabolism.
  13. A two-trick pony: lysosomal protease cathepsin B possesses surprising ligase activity.
  14. Transcriptome of HPβCD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics.
  15. MiR-592 activates the mTOR kinase, ERK1/ERK2 kinase signaling and imparts neuronal differentiation signature characteristic of group 4 medulloblastoma.
  16. Shigella escapes lysosomal degradation through inactivation of Rab31 by IpaH4.5.
  17. Specific KIF1A-adaptor interactions control selective cargo recognition.
  18. Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias.
  19. Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts.
  20. Simultaneous Visualization of Mitochondria and Lysosome by a Single Cyanine Dye: The Impact of the Donor Group (-NR2) Towards Organelle Selectivity.
  21. Loss of PIKfyve drives the spongiform degeneration in prion diseases.
  22. How the vacuole ESCRTs its own proteins to their final destination.
  23. Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9.
  24. CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.
  25. Ubiquitination-Dependent Regulation of Small GTPases in Membrane Trafficking: From Cell Biology to Human Diseases.
  26. Unbiased proteomic and phosphoproteomic analysis identifies response signatures and novel susceptibilities after combined MEK and mTOR inhibition in BRAFV600E mutant glioma.
  27. Neuronal VCP loss of function recapitulates FTLD-TDP pathology.
  28. The TOR-dependent phosphoproteome and regulation of cellular protein synthesis.
  29. Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
  30. A novel amino acid signaling process governs glucose-6-phosphatase transcription.
  31. Molecular probes for selective detection of cysteine cathepsins.
  1. Nat Commun. 2021 Jul 23. 12(1): 4493
    ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability.
    Nazmiye Özkan, Max Koppers, Inge van Soest, Alexandra van Harten, Daphne Jurriens, Nalan Liv, Judith Klumperman, Lukas C Kapitein, Casper C Hoogenraad, Ginny G Farías.
      Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.
    DOI:  https://doi.org/10.1038/s41467-021-24713-5
  2. PLoS Biol. 2021 Jul;19(7): e3001287
    α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes.
    Aysegul Dilsizoglu Senol, Maura Samarani, Sylvie Syan, Carlos M Guardia, Takashi Nonaka, Nalan Liv, Patricia Latour-Lambert, Masato Hasegawa, Judith Klumperman, Juan S Bonifacino, Chiara Zurzolo.
      The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a "prion-like" manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils' transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.
    DOI:  https://doi.org/10.1371/journal.pbio.3001287
  3. PLoS Biol. 2021 Jul 23. 19(7): e3001361
    A  conserved ubiquitin- and ESCRT-dependent pathway internalizes human lysosomal membrane proteins for degradation.
    Weichao Zhang, Xi Yang, Liang Chen, Yun-Yu Liu, Varsha Venkatarangan, Lucas Reist, Phyllis Hanson, Haoxing Xu, Yanzhuang Wang, Ming Li.
      The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate its membrane proteins is poorly understood. In this study, we performed a cycloheximide (CHX) chase assay to measure the half-lives of approximately 30 human lysosomal membrane proteins (LMPs) and identified RNF152 and LAPTM4A as short-lived membrane proteins. The degradation of both proteins is ubiquitin dependent. RNF152 is a transmembrane E3 ligase that ubiquitinates itself, whereas LAPTM4A uses its carboxyl-terminal PY motifs to recruit NEDD4-1 for ubiquitination. After ubiquitination, they are internalized into the lysosome lumen by the endosomal sorting complexes required for transport (ESCRT) machinery for degradation. Strikingly, when ectopically expressed in budding yeast, human RNF152 is still degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.
    DOI:  https://doi.org/10.1371/journal.pbio.3001361
  4. Nature. 2021 Jul 21.
    Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.
    Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J Repa, Nan Yan.
      The classic mode of STING activation is through binding the cyclic dinucleotide 2'3'-cyclic GMP-AMP (cGAMP), produced by the DNA sensor cyclic GMP-AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann-Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 'primes' STING signalling by physically linking or 'tethering' STING to SREBP2 trafficking. Loss of NPC1 protein also 'boosts' STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1-/- mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1-/- mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.
    DOI:  https://doi.org/10.1038/s41586-021-03762-2
  5. Front Cell Dev Biol. 2021 ;9 655731
    The mTOR-Autophagy Axis and the Control of Metabolism.
    Nerea Deleyto-Seldas, Alejo Efeyan.
      The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.
    Keywords:  autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients
    DOI:  https://doi.org/10.3389/fcell.2021.655731
  6. Sci Rep. 2021 Jul 21. 11(1): 14827
    VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma.
    Athina Ganner, Christina Gehrke, Marinella Klein, Lena Thegtmeier, Tanja Matulenski, Laura Wingendorf, Lu Wang, Felicitas Pilz, Lars Greidl, Lisa Meid, Fruzsina Kotsis, Gerd Walz, Ian J Frew, Elke Neumann-Haefelin.
      Inactivation of the tumor suppressor von Hippel-Lindau (VHL) gene is a key event in hereditary and sporadic clear cell renal cell carcinomas (ccRCC). The mechanistic target of rapamycin (mTOR) signaling pathway is a fundamental regulator of cell growth and proliferation, and hyperactivation of mTOR signaling is a common finding in VHL-dependent ccRCC. Deregulation of mTOR signaling correlates with tumor progression and poor outcome in patients with ccRCC. Here, we report that the regulatory-associated protein of mTOR (RAPTOR) is strikingly repressed by VHL. VHL interacts with RAPTOR and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling. Consistent with hyperactivation of mTORC1 signaling in VHL-deficient ccRCC, we observed that loss of vhl-1 function in C. elegans increased mTORC1 activity, supporting an evolutionary conserved mechanism. Our work reveals important new mechanistic insight into deregulation of mTORC1 signaling in ccRCC and links VHL directly to the control of RAPTOR/mTORC1. This may represent a novel mechanism whereby loss of VHL affects organ integrity and tumor behavior.
    DOI:  https://doi.org/10.1038/s41598-021-94132-5
  7. Nature. 2021 Jul 21.
    SAR1B senses leucine levels to regulate mTORC1 signalling.
    Jie Chen, Yuhui Ou, Rong Luo, Jie Wang, Dong Wang, Jialiang Guan, Yi Li, Peixue Xia, Peng R Chen, Ying Liu.
      The mTOR complex 1 (mTORC1) controls cell growth in response to amino acid levels1. Here we report SAR1B as a leucine sensor that regulates mTORC1 signalling in response to intracellular levels of leucine. Under conditions of leucine deficiency, SAR1B inhibits mTORC1 by physically targeting its activator GATOR2. In conditions of leucine sufficiency, SAR1B binds to leucine, undergoes a conformational change and dissociates from GATOR2, which results in mTORC1 activation. SAR1B-GATOR2-mTORC1 signalling is conserved in nematodes and has a role in the regulation of lifespan. Bioinformatic analysis reveals that SAR1B deficiency correlates with the development of lung cancer. The silencing of SAR1B and its paralogue SAR1A promotes mTORC1-dependent growth of lung tumours in mice. Our results reveal that SAR1B is a conserved leucine sensor that has a potential role in the development of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-021-03768-w
  8. Proc Natl Acad Sci U S A. 2021 Jul 27. pii: e2020891118. [Epub ahead of print]118(30):
    Tsc1 regulates tight junction independent of mTORC1.
    Mingqiang Lai, Wenchong Zou, Zelong Han, Ling Zhou, Zeyou Qiu, Juan Chen, Sheng Zhang, Pinglin Lai, Kai Li, Yue Zhang, Li Liang, Yu Jiang, Zhipeng Zou, Xiaochun Bai.
      Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn's disease-like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn's disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.
    Keywords:  Myo6; Tsc1; cell adhesion; mTORC1; tight junction–related disease
    DOI:  https://doi.org/10.1073/pnas.2020891118
  9. J Biol Chem. 2021 Jul 20. pii: S0021-9258(21)00795-X. [Epub ahead of print] 100993
    Delivering progranulin to neuronal lysosomes protects against excitotoxicity.
    Skylar E Davis, Jonathan R Roth, Qays Aljabi, Ahmad R Hakim, Katherine E Savell, Jeremy J Day, Andrew E Arrant.
      Loss-of-function mutations in progranulin (GRN) are a major genetic cause of frontotemporal dementia (FTD), possibly due to loss of progranulin's neurotrophic and anti-inflammatory effects. Progranulin promotes neuronal growth and protects against excitotoxicity and other forms of injury. It is unclear if these neurotrophic effects are mediated through cellular signaling or through promotion of lysosomal function. Progranulin is a secreted pro-protein that may activate neurotrophic signaling through cell-surface receptors. However, progranulin is efficiently trafficked to lysosomes and is necessary for maintaining lysosomal function. To determine which of these mechanisms mediates progranulin's protection against excitotoxicity, we generated lentiviral vectors expressing progranulin (PGRN) or lysosome-targeted progranulin (L-PGRN). L-PGRN was generated by fusing the LAMP-1 transmembrane and cytosolic domains to the C-terminus of progranulin. L-PGRN exhibited no detectable secretion, but was delivered to lysosomes and processed into granulins. PGRN and L-PGRN protected against NMDA excitotoxicity in rat primary cortical neurons, but L-PGRN had more consistent protective effects than PGRN. L-PGRN's protective effects were likely mediated through the autophagy-lysosomal pathway. In control neurons, an excitotoxic dose of NMDA stimulated autophagy, and inhibiting autophagy with 3-methyladenine reduced excitotoxic cell death. L-PGRN blunted the autophagic response to NMDA and occluded the protective effect of 3-methyladenine. This was not due to a general impairment of autophagy, as L-PGRN increased basal autophagy and did not alter autophagy after nutrient starvation. These data show that progranulin's protection against excitotoxicity does not require extracellular progranulin, but is mediated through lysosomes, providing a mechanistic link between progranulin's lysosomal and neurotrophic effects.
    Keywords:  Autophagy; Cell Death; Excitotoxicity; Frontotemporal dementia; Lysosome; Neurodegenerative disease; Progranulin; Protein Secretion
    DOI:  https://doi.org/10.1016/j.jbc.2021.100993
  10. Neurosci Lett. 2021 Jul 15. pii: S0304-3940(21)00495-X. [Epub ahead of print] 136117
    CLN3, at the crossroads of endocytic trafficking.
    Susan L Cotman, Stephane Lefrancois.
      The CLN3 gene was identified over two decades ago, but the primary function of the CLN3 protein remains unknown. Recessive inheritance of loss of function mutations in CLN3 are responsible for juvenile neuronal ceroid lipofuscinosis (Batten disease, or CLN3 disease), a fatal childhood onset neurodegenerative disease causing vision loss, seizures, progressive dementia, motor function loss and premature death. CLN3 is a multipass transmembrane protein that primarily localizes to endosomes and lysosomes. Defects in endocytosis, autophagy, and lysosomal function are common findings in CLN3-deficiency model systems. However, the molecular mechanisms underlying these defects have not yet been fully elucidated. In this mini-review, we will summarize the current understanding of the CLN3 protein interaction network and discuss how this knowledge is starting to delineate the molecular pathogenesis of CLN3 disease. Accumulating evidence strongly points towards CLN3 playing a role in regulation of the cytoskeleton and cytoskeletal associated proteins to tether cellular membranes, regulation of membrane complexes such as channels/transporters, and modulating the function of small GTPases to effectively mediate vesicular movement and membrane dynamics.
    Keywords:  CLN3; actin; autophagy; cytoskeleton; endocytosis; intracellular trafficking; ion channels
    DOI:  https://doi.org/10.1016/j.neulet.2021.136117
  11. Nature. 2021 Jul 21.
    How the amino acid leucine activates the key cell-growth regulator mTOR.
    Tibor Vellai.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-021-01943-7
  12. J Immunol. 2021 Jul 21. pii: ji2100230. [Epub ahead of print]
    mTORC1 Signaling Regulates Proinflammatory Macrophage Function and Metabolism.
    Samuel L Collins, Min-Hee Oh, Im-Hong Sun, Yee Chan-Li, Liang Zhao, Jonathan D Powell, Maureen R Horton.
      Metabolic programming is integrally linked to immune cell function. Nowhere is this clearer than in the differentiation of macrophages. Proinflammatory M1 macrophages primarily use glycolysis as a rapid energy source but also to generate antimicrobial compounds, whereas alternatively activated M2 macrophages primarily rely on oxidative phosphorylation for the longevity required for proper wound healing. mTOR signaling has been demonstrated to be a key regulator of immune cell metabolism and function. mTORC2 signaling is required for the generation of M2 macrophages, whereas the role of mTORC1 signaling, a key regulator of glycolysis, has been controversial. By using genetic deletion of mTORC1 signaling in C57BL/6 mouse macrophages, we observed enhanced M1 macrophage function in vitro and in vivo. Surprisingly, this enhancement occurred despite a significant defect in M1 macrophage glycolytic metabolism. Mechanistically, enhanced M1 function occurred because of inhibition of the class III histone deacetylases the sirtuins, resulting in enhanced histone acetylation. Our findings provide a counterpoint to the paradigm that enhanced immune cell function must occur in the presence of increased cellular metabolism and identifies a potential, pharmacologic target for the regulation of inflammatory responses.
    DOI:  https://doi.org/10.4049/jimmunol.2100230
  13. RSC Chem Biol. 2021 Apr 01. 2(2): 606-611
    A two-trick pony: lysosomal protease cathepsin B possesses surprising ligase activity.
    Tyler R Lambeth, Zhefu Dai, Yong Zhang, Ryan R Julian.
      Cathepsin B is an important protease within the lysosome, where it helps recycle proteins to maintain proteostasis. It is also known to degrade proteins elsewhere but has no other known functionality. However, by carefully monitoring peptide digestion with liquid chromatography and mass spectrometry, we observed the synthesis of novel peptides during cathepsin B incubations. This ligation activity was explored further with a variety of peptide substrates to establish mechanistic details and was found to operate through a two-step mechanism with proteolysis and ligation occurring separately. Further explorations using varied sequences indicated increased affinity for some substrates, though all were found to ligate to some extent. Finally, experiments with a proteolytically inactive form of the enzyme yielded no ligation, indicating that the ligation reaction occurs in the same active site but in the reverse direction of proteolysis. These results clearly establish that in its native form cathepsin B can act as both a protease and ligase, although protease action eventually dominates over longer periods of time.
    DOI:  https://doi.org/10.1039/d0cb00224k
  14. Hum Mol Genet. 2021 Jul 22. pii: ddab194. [Epub ahead of print]
    Transcriptome of HPβCD-treated Niemann-pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics.
    NISC Comparative Sequencing Program
      The rare, fatal neurodegenerative disorder Niemann-Pick disease type C1 (NPC1) arises from lysosomal accumulation of unesterified cholesterol and glycosphingolipids. These subcellular pathologies lead to phenotypes of hepatosplenomegaly, neurological degeneration and premature death. The timing and severity of NPC1 clinical presentation is extremely heterogeneous. This study analyzed RNA-Seq data from 42 NPC1 patient-derived, primary fibroblast cell lines to determine transcriptional changes induced by treatment with 2-hydroxypropyl-β-cyclodextrin (HPβCD), a compound currently under investigation in clinical trials. A total of 485 HPβCD-responsive genes were identified. Pathway enrichment analysis of these genes showed significant involvement in cholesterol and lipid biosynthesis. Furthermore, immunohistochemistry of the cerebellum as well as measurements of serum from Npc1m1N null mice treated with HPβCD and adeno-associated virus (AAV) gene therapy suggests that one of the identified genes, GPNMB, may serve as a useful biomarker of treatment response in NPC1 disease. Overall, this large NPC1 patient-derived dataset provides a comprehensive foundation for understanding the genomic response to HPβCD treatment.
    DOI:  https://doi.org/10.1093/hmg/ddab194
  15. Hum Mol Genet. 2021 Jul 19. pii: ddab201. [Epub ahead of print]
    MiR-592 activates the mTOR kinase, ERK1/ERK2 kinase signaling and imparts neuronal differentiation signature characteristic of group 4 medulloblastoma.
    Raikamal Paul, Purna Bapat, Akash Deogharkar, Sadaf Kazi, Satish Kumar Vishram Singh, Tejpal Gupta, Rakesh Jalali, Epari Sridhar, Aliasgar Moiyadi, Prakash Shetty, Neelam Vishwanath Shirsat.
      Medulloblastoma, a common malignant brain tumor in children, consists of four molecular subgroups WNT, SHH, Group 3 and Group 4. Group 3, Group 4 tumors have an overlap in their expression profiles and genetic alterations but differ significantly in their clinical characteristics, with Group 3 having the worst five-year overall survival of less than 60%. MiR-592 is overexpressed predominantly in Group 4 tumors. MiR-592 expression reduced the anchorage-independent growth, invasion potential, and tumorigenicity of Group 3 medulloblastoma cells. DEPTOR, an endogenous inhibitor of the mTOR kinase, and EML1 were identified as novel targets of miR-592. The miR-592 mediated decrease in the DEPTOR expression levels activated both mTORC1 and mTORC2 complex in medulloblastoma cells. However, the miR-592 expression also decreased the AKT kinase activity, likely to be due to the activation of the inhibitory feedback of the mTOR signaling. MiR-592 expression upregulated several neuronal differentiation-related genes, a characteristic of Group 4 medulloblastoma in Group 3 cell lines. The expression of miR-592 also upregulated the activity of ERK1/ERK2 kinases indicating activation of the MAPK signaling pathway. The inhibition of MAPK signaling by the ERK1/ERK2 inhibitor and mTOR signaling by rapamycin abrogated the miR-592-mediated upregulation of neuronal differentiation-related genes. Group 4 medulloblastomas showed higher activity of the mTOR and MAPK signaling compared to Group 3 tumors. Thus, miR-592 overexpression appears to be a driver event and a determining factor of Group 4 biology, which activates the mTOR and MAPK signaling pathways and thereby imparts its characteristic expression profile of neuronal differentiation-related genes.
    DOI:  https://doi.org/10.1093/hmg/ddab201
  16. J Med Microbiol. 2021 Jul;70(7):
    Shigella escapes lysosomal degradation through inactivation of Rab31 by IpaH4.5.
    Jin Sun, Xiaolin Wang, Haotian Lin, Luming Wan, Ji Chen, Xiaopan Yang, Dongyu Li, Yanhong Zhang, Xiang He, Bin Wang, Mingxin Dong, Hui Zhong, Congwen Wei.
      Introduction.Shigella flexneri is an intracellular bacterial pathogen that utilizes a type III secretion apparatus to inject effector proteins into host cells.Hypothesis/Gap Statement. The T3SS effector IpaH4.5 is important for the virulence of Shigella.Aim. This study aimed to elucidate the molecular mechanism and host target of the IpaH4.5 as well as its roles in S. flexneri infection.Methodology. The GAP assay was used to identify substrate Rab GTPases of IpaH4.5. A coimmunoprecipitation assay was applied to identify the interaction of Rab GTPases with IpaH4.5. A confocal microscopy analysis was used to assess the effects of IpaH4.5 on mannose 6-phosphate receptor (MPR) trafficking. To identify the effects of IpaH4.5 GAP activity on the activity of lysosomal cathepsin B, the Magic Red-RR assay was used. Finally, the intracellular persistence assay was used to identify IpaH4.5 GAP activity in S. flexneri intracellular growth.Results. We found that the effector IpaH4.5 disrupts MPR trafficking and lysosomal function, thereby counteracting host lysosomal degradation. IpaH4.5 harbours TBC-like dual-finger motifs and exhibits potent RabGAP activities towards Rab31. IpaH4.5 disrupts the transport of the cation-dependent mannose 6-phosphate receptor (CD-MPR) from the Golgi to the endosome by targeting Rab31, thereby attenuating lysosomal function. As a result, the intracellular persistence of S. flexneri requires IpaH4.5 TBC-like GAP activity to mediate bacterial escape from host lysosome-mediated elimination.Conclusion. We identified an unknown function of IpaH4.5 and its potential role in S. flexneri infection.
    Keywords:  IpaH4.5; Rab31; Shigella; infection
    DOI:  https://doi.org/10.1099/jmm.0.001382
  17. J Cell Biol. 2021 Oct 04. pii: e202105011. [Epub ahead of print]220(10):
    Specific KIF1A-adaptor interactions control selective cargo recognition.
    Jessica J A Hummel, Casper C Hoogenraad.
      Intracellular transport in neurons is driven by molecular motors that carry many different cargos along cytoskeletal tracks in axons and dendrites. Identifying how motors interact with specific types of transport vesicles has been challenging. Here, we use engineered motors and cargo adaptors to systematically investigate the selectivity and regulation of kinesin-3 family member KIF1A-driven transport of dense core vesicles (DCVs), lysosomes, and synaptic vesicles (SVs). We dissect the role of KIF1A domains in motor activity and show that CC1 regulates autoinhibition, CC2 regulates motor dimerization, and CC3 and PH mediate cargo binding. Furthermore, we identify that phosphorylation of KIF1A is critical for binding to vesicles. Cargo specificity is achieved by specific KIF1A adaptors; MADD/Rab3GEP links KIF1A to SVs, and Arf-like GTPase Arl8A mediates interactions with DCVs and lysosomes. We propose a model where motor dimerization, posttranslational modifications, and specific adaptors regulate selective KIF1A cargo trafficking.
    DOI:  https://doi.org/10.1083/jcb.202105011
  18. Front Oncol. 2021 ;11 694526
    Amino Acid Metabolic Vulnerabilities in Acute and Chronic Myeloid Leukemias.
    Aboli Bhingarkar, Hima V Vangapandu, Sanjay Rathod, Keito Hoshitsuki, Christian A Fernandez.
      Amino acid (AA) metabolism plays an important role in many cellular processes including energy production, immune function, and purine and pyrimidine synthesis. Cancer cells therefore require increased AA uptake and undergo metabolic reprogramming to satisfy the energy demand associated with their rapid proliferation. Like many other cancers, myeloid leukemias are vulnerable to specific therapeutic strategies targeting metabolic dependencies. Herein, our review provides a comprehensive overview and TCGA data analysis of biosynthetic enzymes required for non-essential AA synthesis and their dysregulation in myeloid leukemias. Furthermore, we discuss the role of the general control nonderepressible 2 (GCN2) and-mammalian target of rapamycin (mTOR) pathways of AA sensing on metabolic vulnerability and drug resistance.
    Keywords:  GCN2; general control non-derepressible 2; mTORC1; myeloid leukemias; non-essential amino acid
    DOI:  https://doi.org/10.3389/fonc.2021.694526
  19. Dis Model Mech. 2021 Jul 01. pii: dmm048997. [Epub ahead of print]14(7):
    Loss of vacuolar-type H+-ATPase induces caspase-independent necrosis-like death of hair cells in zebrafish neuromasts.
    Peu Santra, Jeffrey D Amack.
      The vacuolar-type H+-ATPase (V-ATPase) is a multi-subunit proton pump that regulates cellular pH. V-ATPase activity modulates several cellular processes, but cell-type-specific functions remain poorly understood. Patients with mutations in specific V-ATPase subunits can develop sensorineural deafness, but the underlying mechanisms are unclear. Here, we show that V-ATPase mutations disrupt the formation of zebrafish neuromasts, which serve as a model to investigate hearing loss. V-ATPase mutant neuromasts are small and contain pyknotic nuclei that denote dying cells. Molecular markers and live imaging show that loss of V-ATPase induces mechanosensory hair cells in neuromasts, but not neighboring support cells, to undergo caspase-independent necrosis-like cell death. This is the first demonstration that loss of V-ATPase can lead to necrosis-like cell death in a specific cell type in vivo. Mechanistically, loss of V-ATPase reduces mitochondrial membrane potential in hair cells. Modulating the mitochondrial permeability transition pore, which regulates mitochondrial membrane potential, improves hair cell survival. These results have implications for understanding the causes of sensorineural deafness, and more broadly, reveal functions for V-ATPase in promoting survival of a specific cell type in vivo.
    Keywords:  Mitochondrial membrane potential; Necrosis-like cell death; Neuromast hair cell; Vacuolar-type H+-ATPase (V-ATPase); Zebrafish
    DOI:  https://doi.org/10.1242/dmm.048997
  20. J Fluoresc. 2021 Jul 23.
    Simultaneous Visualization of Mitochondria and Lysosome by a Single Cyanine Dye: The Impact of the Donor Group (-NR2) Towards Organelle Selectivity.
    Chathura S Abeywickrama, Hannah J Baumann, Yi Pang.
      A benzothiazolium-based hemicyanine dye (probe 3) has been synthesized by attaching a morpholine group into a phenyl benzothiazolium skeleton. Probe 3 exhibited interesting photophysical characteristics including red emission (λem ≈600 nm), enhanced Stokes shift (Δλ ≈80 nm) and sensitivity to solvent polarity. Although the probe 3 exhibited almost no emission in aqueous environments (φfl ≈0.002), its fluorescence could be increased by ≈50 fold in organic solvents (φfl ≈0.10), making it possible for live cell imaging under wash-free conditions. Probe 3 exhibited excellent ability to visualize cellular mitochondria and lysosomes simultaneously, as observed from fluorescence confocal microscopy. In addition, probe 3 also exhibited good biocompatibility (calculated LC50 > 20 µM) and high photostability.
    Keywords:  Cyanine dyes; Fluorescence confocal microscopy; Lysosome; Mitochondria; Simultaneous detection; Wash-free application
    DOI:  https://doi.org/10.1007/s10895-021-02786-1
  21. EMBO Mol Med. 2021 Jul 22. e14714
    Loss of PIKfyve drives the spongiform degeneration in prion diseases.
    Asvin K K Lakkaraju, Karl Frontzek, Emina Lemes, Uli Herrmann, Marco Losa, Rajlakshmi Marpakwar, Adriano Aguzzi.
      Brain-matter vacuolation is a defining trait of all prion diseases, yet its cause is unknown. Here, we report that prion infection and prion-mimetic antibodies deplete the phosphoinositide kinase PIKfyve-which controls endolysosomal maturation-from mouse brains, cultured cells, organotypic brain slices, and brains of Creutzfeldt-Jakob disease victims. We found that PIKfyve is acylated by the acyltransferases zDHHC9 and zDHHC21, whose juxtavesicular topology is disturbed by prion infection, resulting in PIKfyve deacylation and rapid degradation, as well as endolysosomal hypertrophy and activation of TFEB-dependent lysosomal enzymes. A protracted unfolded protein response (UPR), typical of prion diseases, also induced PIKfyve deacylation and degradation. Conversely, UPR antagonists restored PIKfyve levels in prion-infected cells. Overexpression of zDHHC9 and zDHHC21, administration of the antiprion polythiophene LIN5044, or supplementation with the PIKfyve reaction product PI(3,5)P2 suppressed prion-induced vacuolation and restored lysosomal homeostasis. Thus, PIKfyve emerges as a central mediator of vacuolation and neurotoxicity in prion diseases.
    Keywords:  neurodegeneration; palmitoylation; prion; spongiosis; unfolded protein response
    DOI:  https://doi.org/10.15252/emmm.202114714
  22. J Cell Biol. 2021 Aug 02. pii: e202105177. [Epub ahead of print]220(8):
    How the vacuole ESCRTs its own proteins to their final destination.
    W Mike Henne.
      Lysosomes (vacuoles in yeast) are master regulators of metabolism and protein turnover, but how they degrade their own resident proteins is unclear. Recently, multiple models have been proposed explaining yeast vacuole protein sorting, but the role of the ESCRT pathway was unclear. In this JCB issue, work from Yang et al. (https://doi.org/10.1083/jcb.202012104) highlights how the ESCRT pathway localizes to the vacuole surface to execute protein sorting of its resident proteins.
    DOI:  https://doi.org/10.1083/jcb.202105177
  23. Nat Commun. 2021 07 19. 12(1): 4389
    Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9.
    Mathilde Mathieu, Nathalie Névo, Mabel Jouve, José Ignacio Valenzuela, Mathieu Maurin, Frederik J Verweij, Roberta Palmulli, Danielle Lankar, Florent Dingli, Damarys Loew, Eric Rubinstein, Gaëlle Boncompain, Franck Perez, Clotilde Théry.
      Despite their roles in intercellular communications, the different populations of extracellular vesicles (EVs) and their secretion mechanisms are not fully characterized: how and to what extent EVs form as intraluminal vesicles of endocytic compartments (exosomes), or at the plasma membrane (PM) (ectosomes) remains unclear. Here we follow intracellular trafficking of the EV markers CD9 and CD63 from the endoplasmic reticulum to their residency compartment, respectively PM and late endosomes. We observe transient co-localization at both places, before they finally segregate. CD9 and a mutant CD63 stabilized at the PM are more abundantly released in EVs than CD63. Thus, in HeLa cells, ectosomes are more prominent than exosomes. By comparative proteomic analysis and differential response to neutralization of endosomal pH, we identify a few surface proteins likely specific of either exosomes (LAMP1) or ectosomes (BSG, SLC3A2). Our work sets the path for molecular and functional discrimination of exosomes and small ectosomes in any cell type.
    DOI:  https://doi.org/10.1038/s41467-021-24384-2
  24. Dis Model Mech. 2021 Jul 01. pii: dmm048603. [Epub ahead of print]14(7):
    CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases.
    Jordan M Wall, Ankita Basu, Elizabeth R M Zunica, Olga S Dubuisson, Kathryn Pergola, Joshua P Broussard, John P Kirwan, Christopher L Axelrod, Alyssa E Johnson.
      Mutations in Valosin Containing Protein (VCP) are associated with several degenerative diseases, including multisystem proteinopathy (MSP-1) and amyotrophic lateral sclerosis. However, patients with VCP mutations vary widely in their pathology and clinical penetrance, making it difficult to devise effective treatment strategies. A deeper understanding of how each mutation affects VCP function could enhance the prediction of clinical outcomes and design of personalized treatment options. The power of a genetically tractable model organism coupled with well-established in vivo assays and a relatively short life cycle make Drosophila an attractive system to study VCP disease pathogenesis. Using CRISPR/Cas9, we have generated individual Drosophila knock-in mutants that include nine hereditary VCP disease mutations. Our models display many hallmarks of VCP-mediated degeneration, including progressive decline in mobility, protein aggregate accumulation and defects in lysosomal and mitochondrial function. We also made some novel and unexpected findings, including nuclear morphology defects and sex-specific phenotypic differences in several mutants. Taken together, the Drosophila VCP disease models generated in this study will be useful for studying the etiology of individual VCP patient mutations and testing potential genetic and/or pharmacological therapies.
    Keywords:   Drosophila ; IBMPFD; Lysosomes; MSP-1; Mitochondria; Ter94; VCP
    DOI:  https://doi.org/10.1242/dmm.048603
  25. Front Cell Dev Biol. 2021 ;9 688352
    Ubiquitination-Dependent Regulation of Small GTPases in Membrane Trafficking: From Cell Biology to Human Diseases.
    Zehui Lei, Jing Wang, Lingqiang Zhang, Cui Hua Liu.
      Membrane trafficking is critical for cellular homeostasis, which is mainly carried out by small GTPases, a class of proteins functioning in vesicle budding, transport, tethering and fusion processes. The accurate and organized membrane trafficking relies on the proper regulation of small GTPases, which involves the conversion between GTP- and GDP-bound small GTPases mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Emerging evidence indicates that post-translational modifications (PTMs) of small GTPases, especially ubiquitination, play an important role in the spatio-temporal regulation of small GTPases, and the dysregulation of small GTPase ubiquitination can result in multiple human diseases. In this review, we introduce small GTPases-mediated membrane trafficking pathways and the biological processes of ubiquitination-dependent regulation of small GTPases, including the regulation of small GTPase stability, activity and localization. We then discuss the dysregulation of small GTPase ubiquitination and the associated human membrane trafficking-related diseases, focusing on the neurological diseases and infections. An in-depth understanding of the molecular mechanisms by which ubiquitination regulates small GTPases can provide novel insights into the membrane trafficking process, which knowledge is valuable for the development of more effective and specific therapeutics for membrane trafficking-related human diseases.
    Keywords:  infections; membrane trafficking; neurological diseases; small GTPase; ubiquitination
    DOI:  https://doi.org/10.3389/fcell.2021.688352
  26. Mol Cell Proteomics. 2021 Jul 20. pii: S1535-9476(21)00095-5. [Epub ahead of print] 100123
    Unbiased proteomic and phosphoproteomic analysis identifies response signatures and novel susceptibilities after combined MEK and mTOR inhibition in BRAFV600E mutant glioma.
    Micah J Maxwell, Antje Arnold, Heather Sweeney, Lijun Chen, Tung-Shing M Lih, Michael Schnaubelt, Charles G Eberhart, Jeffrey A Rubens, Hui Zhang, David J Clark, Eric H Raabe.
      The mitogen-activated protein kinase (MAPK) pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the BRAF component of the pathway. MEK inhibition is initially effective in targeting these cancers, but reflexive activation of mTOR signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mTORC1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAFV600E mutant glioma model. To elucidate the mechanism of action of this combination therapy and understand the ensuing tumor response, we performed comprehensive unbiased proteomic and phosphoproteomic characterization of BRAFV600E mutant glioma xenografts after short-course treatment with trametinib and TAK228. We identified 13,313 proteins and 30,928 localized phosphosites, of which 12,526 proteins and 17,444 phosphosites were quantified across all samples (data available via ProteomeXchange; identifier PXD022329). We identified distinct response signatures for each monotherapy and combination therapy and validated that combination treatment inhibited activation of the MAPK and mTOR pathways. Combination therapy also increased apoptotic signaling, suppressed angiogenesis signaling, and broadly suppressed the activity of the cyclin-dependent kinases. In response to combination therapy, both epidermal growth factor receptor and class 1 histone deacetylase proteins were activated. This study reports a detailed (phospho)proteomic analysis of the response of BRAFV600E mutant glioma to combined MEK and mTOR pathway inhibition and identifies new targets for the development of rational combination therapies for BRAF-driven tumors.
    DOI:  https://doi.org/10.1016/j.mcpro.2021.100123
  27. Cell Rep. 2021 Jul 20. pii: S2211-1247(21)00797-X. [Epub ahead of print]36(3): 109399
    Neuronal VCP loss of function recapitulates FTLD-TDP pathology.
    Abubakar Wani, Jiang Zhu, Jason D Ulrich, Abdallah Eteleeb, Andrew D Sauerbeck, Sydney J Reitz, Khalid Arhzaouy, Chiseko Ikenaga, Carla M Yuede, Sara K Pittman, Feng Wang, Shan Li, Bruno A Benitez, Carlos Cruchaga, Terrance T Kummer, Oscar Harari, Tsui-Fen Chou, Rolf Schröder, Christoph S Clemen, Conrad C Weihl.
      The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
    Keywords:  FTD; FTLD; TDP-43; VCP; autophagy; multisystem proteinopathy; neurodegeneration; progranulin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109399
  28. EMBO J. 2021 Jul 23. e107911
    The TOR-dependent phosphoproteome and regulation of cellular protein synthesis.
    Tiffany Mak, Andrew W Jones, Paul Nurse.
      Cell growth is orchestrated by a number of interlinking cellular processes. Components of the TOR pathway have been proposed as potential regulators of cell growth, but little is known about their immediate effects on protein synthesis in response to TOR-dependent growth inhibition. Here, we present a resource providing an in-depth characterisation of Schizosaccharomyces pombe phosphoproteome in relation to changes observed in global cellular protein synthesis upon TOR inhibition. We find that after TOR inhibition, the rate of protein synthesis is rapidly reduced and that notable phosphorylation changes are observed in proteins involved in a range of cellular processes. We show that this reduction in protein synthesis rates upon TOR inhibition is not dependent on S6K activity, but is partially dependent on the S. pombe homologue of eIF4G, Tif471. Our study demonstrates the impact of TOR-dependent phospho-regulation on the rate of protein synthesis and establishes a foundational resource for further investigation of additional TOR-regulated targets both in fission yeast and other eukaryotes.
    Keywords:  TOR regulation; phosphoproteomics; protein synthesis
    DOI:  https://doi.org/10.15252/embj.2021107911
  29. Cell. 2021 Jul 14. pii: S0092-8674(21)00796-0. [Epub ahead of print]
    Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
    Charles L Evavold, Iva Hafner-Bratkovič, Pascal Devant, Jasmin M D'Andrea, Elsy M Ngwa, Elvira Boršić, John G Doench, Martin W LaFleur, Arlene H Sharpe, Jay R Thiagarajah, Jonathan C Kagan.
      The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).
    Keywords:  gasdermin D; inflammasomes; inflammation; innate immunity; macrophages; mtorc1; pyroptosis; ragulator; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cell.2021.06.028
  30. iScience. 2021 Jul 23. 24(7): 102778
    A novel amino acid signaling process governs glucose-6-phosphatase transcription.
    Sara Fukushima, Hiroki Nishi, Mikako Kumano, Daisuke Yamanaka, Naoyuki Kataoka, Fumihiko Hakuno, Shin-Ichiro Takahashi.
      Emerging evidence has shown that amino acids act as metabolic regulatory signals. Here, we showed that glucose-6-phosphatase (G6Pase) mRNA levels in cultured hepatocyte models were downregulated in an amino-acid-depleted medium. Inversely, stimulation with amino acids increased G6Pase mRNA levels, demonstrating that G6Pase mRNA level is directly controlled by amino acids in a reversible manner. Promoter assay revealed that these amino-acid-mediated changes in G6Pase mRNA levels were attributable to transcriptional regulation, independent of canonical hormone signaling pathways. Metabolomic analysis revealed that amino acid starvation induces a defect in the urea cycle, decreasing ornithine, a major intermediate, and supplementation of ornithine in an amino-acid-depleted medium fully rescued G6Pase mRNA transcription, similar to the effects of amino acid stimulation. This pathway was also independent of established mammalian target of rapamycin complex 1 pathway. Collectively, we present a hypothetical concept of "metabolic regulatory amino acid signal," possibly mediated by ornithine.
    Keywords:  Biochemistry; Biological Sciences; Cell Biology; Metabolomics; Molecular Biology; Molecular Mechanism of Gene Regulation; Natural Sciences
    DOI:  https://doi.org/10.1016/j.isci.2021.102778
  31. Org Biomol Chem. 2021 Jul 21. 19(28): 6182-6205
    Molecular probes for selective detection of cysteine cathepsins.
    Kelton A Schleyer, Lina Cui.
      Cysteine cathepsins are proteases critical in physiopathological processes and show potential as targets or biomarkers for diseases and medical conditions. The 11 members of the cathepsin family are redundant in some cases but remarkably independent of others, demanding the development of both pan-cathepsin targeting tools as well as probes that are selective for specific cathepsins with little off-target activity. This review addresses the diverse design strategies that have been employed to accomplish this tailored selectivity among cysteine cathepsin targets and the imaging modalities incorporated. The power of these diverse tools is contextualized by briefly highlighting the nature of a few prominent cysteine cathepsins, their involvement in select diseases, and the application of cathepsin imaging probes in research spanning basic biochemical studies to clinical applications.
    DOI:  https://doi.org/10.1039/d1ob00225b
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