bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2022–11–20
twelve papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. The lysosomal degraders.
  2. Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2.
  3. Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage.
  4. Organelle homeostasis: from cellular mechanisms to disease.
  5. Silencing RIPK1/mTORC1 signalling attenuated the inflammation and oxidative stress in diabetic cardiomyopathy.
  6. Choreographing the motor-driven endosomal dance.
  7. Iron homeostasis in the heart: Molecular mechanisms and pharmacological implications.
  8. MCOLN3/TRPML3 bridges the regulation of autophagosome biogenesis by PtdIns3P and the calcium channel.
  9. Molecular interplays of the Entamoeba histolytica endosomal sorting complexes required for transport during phagocytosis.
  10. Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning.
  11. Enhanced lysosome biogenesis ameliorates neurodegenerative diseases.
  12. SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome-lysosome fusion.
  1. Nat Biotechnol. 2022 Nov 17.
    The lysosomal degraders.
    Ken Garber.
      
    DOI:  https://doi.org/10.1038/s41587-022-01594-7
  2. EMBO J. 2022 Nov 17. 41(22): e111476
    Oxidative stress-induced phosphorylation of JIP4 regulates lysosomal positioning in coordination with TRPML1 and ALG2.
    Yukiko Sasazawa, Sanae Souma, Norihiko Furuya, Yoshiki Miura, Saiko Kazuno, Soichiro Kakuta, Ayami Suzuki, Ryota Hashimoto, Hiroko Hirawake-Mogi, Yuki Date, Masaya Imoto, Takashi Ueno, Tetsushi Kataura, Viktor I Korolchuk, Taiji Tsunemi, Nobutaka Hattori, Shinji Saiki.
      Retrograde transport of lysosomes is recognised as a critical autophagy regulator. Here, we found that acrolein, an aldehyde that is significantly elevated in Parkinson's disease patient serum, enhances autophagy by promoting lysosomal clustering around the microtubule organising centre via a newly identified JIP4-TRPML1-ALG2 pathway. Phosphorylation of JIP4 at T217 by CaMK2G in response to Ca2+ fluxes tightly regulated this system. Increased vulnerability of JIP4 KO cells to acrolein indicated that lysosomal clustering and subsequent autophagy activation served as defence mechanisms against cytotoxicity of acrolein itself. Furthermore, the JIP4-TRPML1-ALG2 pathway was also activated by H2 O2 , indicating that this system acts as a broad mechanism of the oxidative stress response. Conversely, starvation-induced lysosomal retrograde transport involved both the TMEM55B-JIP4 and TRPML1-ALG2 pathways in the absence of the JIP4 phosphorylation. Therefore, the phosphorylation status of JIP4 acts as a switch that controls the signalling pathways of lysosoma l distribution depending on the type of autophagy-inducing signal.
    Keywords:  JIP4; Parkinson's disease; autophagy; lysosomal positioning; oxidative stress
    DOI:  https://doi.org/10.15252/embj.2022111476
  3. Autophagy. 2022 Nov 17.
    Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage.
    Jingyue Jia, Fulong Wang, Zambarlal Bhujabal, Ryan Peters, Michal Mudd, Thabata Duque, Lee Allers, Ruheena Javed, Michelle Salemi, Christian Behrends, Brett Phinney, Terje Johansen, Vojo Deretic.
      The functions of mammalian Atg8 proteins (mATG8s) expand beyond canonical autophagy and include processes collectively referred to as Atg8ylation. Global modulation of protein synthesis under stress conditions is governed by MTOR and liquid-liquid phase separated condensates containing ribonucleoprotein particles known as stress granules (SGs). We report that lysosomal damage induces SGs acting as a hitherto unappreciated inhibitor of protein translation via EIF2A/eIF2α phosphorylation while favoring an ATF4-dependent integrated stress response. SGs are induced by lysosome-damaging agents, SARS-CoV-2 open reading frame 3a protein (ORF3a) expression, Mycobacterium tuberculosis infection, and exposure to proteopathic MAPT/tau. Proteomic studies revealed recruitment to damaged lysosomes of the core SG proteins NUFIP2 and G3BP1 along with the GABARAPs of the mATG8 family. The recruitment of these proteins is independent of SG condensates or canonical autophagy. GABARAPs interact directly with NUFIP2 and G3BP1 whereas Atg8ylation is needed for their recruitment to damaged lysosomes. At the lysosome, NUFIP2 contributes to MTOR inactivation together with LGALS8 (galectin 8) via the Ragulator-RRAGA-RRAGB complex. The separable functions of NUFIP2 and G3BP1 in SG formation vis-a-vis their role in MTOR inactivation are governed by GABARAP and Atg8ylation. Thus, cells employ membrane Atg8ylation to control and coordinate SG and MTOR responses to lysosomal damage.
    Keywords:  Atg8ylation; MTOR; Mycobacterium tuberculosis; NUFIP2; PKR; SARS-CoV-2 ORF3a; integrated stress response; lysosomal damage; proteopathic tau; stress granules
    DOI:  https://doi.org/10.1080/15548627.2022.2148900
  4. FEBS J. 2022 Nov;289(22): 6822-6831
    Organelle homeostasis: from cellular mechanisms to disease.
    Emma Burbridge, Colin Adrain.
      The major criterion that distinguishes eukaryotes from prokaryotes is the presence of organelles in the former. Organelles provide a compartment in which biochemical processes are corralled within bespoke biophysical conditions and act as storage depots, powerhouses, waste storage/recycling units and innate immune signalling hubs. A key challenge faced by organelles is to define, and then retain, their identity; this is mediated by complex proteostasis mechanisms including the import of an organelle-specific proteome, the exclusion of non-organellar proteins and the removal of misfolded proteins via dedicated quality control mechanisms. This Special Issue on Organelle Homeostasis provides an engaging, eclectic, yet integrative, perspective on organelle homeostasis in a range of organelles including those from the secretory and endocytic pathways, mitochondria, the autophagy-lysosomal pathway and the nucleus and its sub-compartments. Some lesser-known organelles including migrasomes (organelles that are released by migrating cells) and GOMED (a Golgi-specific form of autophagy) are also introduced. In the spirit of the principles of organelle biology, we hope you find the reviews in this Issue both encapsulating and captivating, and we thank the authors for their excellent contributions.
    Keywords:  endoplasmic reticulum; mitochondria; nucleus; organelle homeostasis; quality control
    DOI:  https://doi.org/10.1111/febs.16667
  5. Exp Cell Res. 2022 Nov 12. pii: S0014-4827(22)00410-4. [Epub ahead of print] 113417
    Silencing RIPK1/mTORC1 signalling attenuated the inflammation and oxidative stress in diabetic cardiomyopathy.
    Qin Liu, Changqing Deng, Xianliang Xing, Yanhui Hu, Zhong Wang, Yingping Liang.
       BACKGROUND: Diabetes cardiomyopathy (DCM) is one of the major risk factors for the heart failure of the diabetic patients. RIPK1 maybe participate in the regulation of the oxidative stress and inflammation during DCM.
    METHODS: H&E and Masson staining were utilized to assess the inflammation and fibrosis in the myocardial tissues. CCK-8 and TUNEL staining were utilized to analyze cell viability and apoptosis, respectively. SOD activity and MDA content were detected utilizing the kits. The formation of autophagosomes was measured by immunofluorescence assay.
    RESULTS: RIPK1 and RPTOR (a component of mTORC1) expression and oxidative stress level were upregulated, but autophagy was decreased in the myocardial tissues of DCM rat characterized by the high body weight and blood glucose, abnormal cardiac function, myocardial inflammation and fibrosis. High glucose (HG) treatment resulted in cell viability and autophagy level decreasing, inflammatory cytokines expression increasing and oxidative stress increasing in cardiac fibroblasts (CFs). Meanwhile, RIPK1 and RPTOR expression also was increased in HG-treated cells. HG-induced CFs apoptosis, inflammation, oxidative stress and the inhibition of HG to cell viability and autophagy was partly reversed by the inhibitor of RIPK1 and mTORC1.
    CONCLUSION: Overall, RIPK1/mTORC1 signalling suppression improved HG-induced apoptosis, inflammation and oxidative stress through activation autophagy. These data provided a reliable evidence that RIPK1 may be a potential target for DCM therapeutic.
    Keywords:  Autophagy; Diabetes cardiomyopathy; Diabetes mellitus; Mammalian target of rapamycin complex 1; Receptor-interacting protein kinase 1
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113417
  6. J Cell Sci. 2023 Mar 01. pii: jcs259689. [Epub ahead of print]136(5):
    Choreographing the motor-driven endosomal dance.
    Marlieke L M Jongsma, Nina Bakker, Jacques Neefjes.
      The endosomal system orchestrates the transport of lipids, proteins and nutrients across the entire cell. Along their journey, endosomes mature, change shape via fusion and fission, and communicate with other organelles. This intriguing endosomal choreography, which includes bidirectional and stop-and-go motions, is coordinated by the microtubule-based motor proteins dynein and kinesin. These motors bridge various endosomal subtypes to the microtubule tracks thanks to their cargo-binding domain interacting with endosome-associated proteins, and their motor domain interacting with microtubules and associated proteins. Together, these interactions determine the mobility of different endosomal structures. In this Review, we provide a comprehensive overview of the factors regulating the different interactions to tune the fascinating dance of endosomes along microtubules.
    Keywords:  Dynactin; Dynein; Endoplasmic reticulum; Endosomes; Kinesin; Membrane contact sites; Microtubules
    DOI:  https://doi.org/10.1242/jcs.259689
  7. J Mol Cell Cardiol. 2022 Nov 11. pii: S0022-2828(22)00552-1. [Epub ahead of print]174 15-24
    Iron homeostasis in the heart: Molecular mechanisms and pharmacological implications.
    Jiawei Zhang, Yijing Song, You Li, Han-Bin Lin, Xuexian Fang.
      Iron is necessary for the life of practically all living things, yet it may also harm people toxically. Accordingly, humans and other mammals have evolved an effective and tightly regulatory system to maintain iron homeostasis in healthy tissues, including the heart. Iron deficiency is common in patients with heart failure, and is associated with worse prognosis in this population; while the prevalence of iron overload-related cardiovascular disorders is also increasing. Therefore, enhancing the therapy of patients with cardiovascular disorders requires a thorough understanding of iron homeostasis. Here, we give readers an overview of the fundamental mechanisms governing systemic iron homeostasis as well as the most recent knowledge about the intake, storage, use, and export of iron from the heart. Genetic mouse models used for investigation of iron metabolism in various in vivo scenarios are summarized and highlighted. We also go through different clinical conditions and therapeutic approaches that target cardiac iron dyshomeostasis. Finally, we conclude the review by outlining the present knowledge gaps and important open questions in this field in order to guide future research on cardiac iron metabolism.
    Keywords:  Cardiovascular diseases; Heart; Iron metabolism; Mitochondrion; Oxidative stress
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.11.001
  8. Autophagy. 2022 Nov 16.
    MCOLN3/TRPML3 bridges the regulation of autophagosome biogenesis by PtdIns3P and the calcium channel.
    Yuchen Lei, Daniel J Klionsky.
      In recent years, an increasing number of studies have started to investigate the roles of ions and ion channels in macroautophagy/autophagy. One finding is that calcium regulates multiple stages of autophagy with lysosomal calcium release being important for autophagosome and lysosome fusion. MCOLN3/TRPML3, as a calcium-permeable channel that is located on both lysosomes and autophagosomes, has been suggested as an autophagy regulator and a candidate to provide the calcium for autophagic fusion, but how this channel is activated remains unclear. In a recent article, Kim et al. demonstrate that MCOLN3 is a PtdIns3P downstream effector, and the activation of its channel function is critical for autophagosome biogenesis.
    Keywords:  Autophagosome; MCOLN3/TRPML3; PtdIns3P; calcium; fusion
    DOI:  https://doi.org/10.1080/15548627.2022.2148808
  9. Front Cell Infect Microbiol. 2022 ;12 855797
    Molecular interplays of the Entamoeba histolytica endosomal sorting complexes required for transport during phagocytosis.
    Cecilia Bañuelos, Abigail Betanzos, Rosario Javier-Reyna, Ausencio Galindo, Esther Orozco.
      Entamoeba histolytica, the causative agent of human amoebiasis, exhibits a continuous membrane remodelling to exert its virulence properties. During this dynamic process, the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is a key player, particularly in phagocytosis, a virulence hallmark of this parasite. In addition to ESCRT, other molecules contribute to membrane remodelling, including the EhADH adhesin, EhRabs, actin, and the lysobisphosphatidic acid (LBPA). The endocytosis of a prey or molecules induces membrane invaginations, resulting in endosome and multivesicular bodies (MVBs) formation for cargo delivery into lysosomes. Alternatively, some proteins are recycled or secreted. Most of these pathways have been broadly characterized in other biological systems, but poorly described in protozoan parasites. Here, we encompass 10 years of ESCRT research in E. histolytica, highlighting the role of the ESCRT-I and ESCRT-III components and the EhADH and EhVps4-ATPase accessory proteins during phagocytosis. In particular, EhADH exhibits a multifunctional role along the endocytic pathway, from cargo recognition to endosome maturation and lysosomal degradation. Interestingly, the interaction of EhADH with EhVps32 seems to shape a concurrent route to the conventional one for MVBs biogenesis, that could optimize their formation. Furthermore, this adhesin is secreted, but its role in this event remains under study. Other components from the endosomal pathway, such as EhVps23 and LBPA, are also secreted. A proteomic approach performed here, using an anti-LBPA antibody, revealed that some proteins related to membrane trafficking, cellular transport, cytoskeleton dynamics, and transcriptional and translational functions are secreted and associated to LBPA. Altogether, the accumulated knowledge around the ESCRT machinery in E. histolytica, points it out as a dynamic platform facilitating the interaction of molecules participating in different cellular events. Seen as an integrated system, ESCRTs lead to a better understanding of E. histolytica phagocytosis.
    Keywords:  EhADH; EhRabs; LBPA; Vps; cargo sorting; endosome maturation; intraluminal vesicles; late endosome/MVB
    DOI:  https://doi.org/10.3389/fcimb.2022.855797
  10. Traffic. 2022 Nov 18.
    Cab45 deficiency leads to the mistargeting of progranulin and prosaposin and aberrant lysosomal positioning.
    Mai Ly Tran, Johanna Tüshaus, Yeongho Kim, Bulat R Ramazanov, Swathi Devireddy, Stefan F Lichtenthaler, Shawn M Ferguson, Julia von Blume.
      The trans-Golgi Network (TGN) sorts molecular "addresses" and sends newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains poorly understood. Recent research has shown that the Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca2+ influx, recruits soluble cargo molecules (clients), and packs them in sphingomyelin-rich transport carriers. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a precise and highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the unprocessed precursors of prosaposin (PSAP) and progranulin (PGRN). In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning. This work uncovers a yet unknown function of Cab45 in regulating lysosomal function.
    Keywords:  Cab45; TGN export; lysosomal hydrolases; progranulin; prosaposin
    DOI:  https://doi.org/10.1111/tra.12873
  11. Aging (Albany NY). 2022 Nov 14. 14
    Enhanced lysosome biogenesis ameliorates neurodegenerative diseases.
    Wenlong Xue, Yang Li.
      
    Keywords:  TFEB; lysosome biogenesis; lysosome-enhancing compounds; neurodegenerative diseases
    DOI:  https://doi.org/10.18632/aging.204389
  12. Cell Death Dis. 2022 Nov 12. 13(11): 953
    SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome-lysosome fusion.
    Patricia González-Rodríguez, Elizabeth Delorme-Axford, Amélie Bernard, Lily Keane, Vassilis Stratoulias, Kathleen Grabert, Pinelopi Engskog-Vlachos, Jens Füllgrabe, Daniel J Klionsky, Bertrand Joseph.
      Macroautophagy/autophagy is an evolutionarily conserved and tightly regulated catabolic process involved in the maintenance of cellular homeostasis whose dysregulation is implicated in several pathological processes. Autophagy begins with the formation of phagophores that engulf cytoplasmic cargo and mature into double-membrane autophagosomes; the latter fuse with lysosomes/vacuoles for cargo degradation and recycling. Here, we report that yeast Set2, a histone lysine methyltransferase, and its mammalian homolog, SETD2, both act as positive transcriptional regulators of autophagy. However, whereas Set2 regulates the expression of several autophagy-related (Atg) genes upon nitrogen starvation, SETD2 effects in mammals were found to be more restricted. In fact, SETD2 appears to primarily regulate the differential expression of protein isoforms encoded by the ATG14 gene. SETD2 promotes the expression of a long ATG14 isoform, ATG14L, that contains an N-terminal cysteine repeats domain, essential for the efficient fusion of the autophagosome with the lysosome, that is absent in the short ATG14 isoform, ATG14S. Accordingly, SETD2 loss of function decreases autophagic flux, as well as the turnover of aggregation-prone proteins such as mutant HTT (huntingtin) leading to increased cellular toxicity. Hence, our findings bring evidence to the emerging concept that the production of autophagy-related protein isoforms can differentially affect core autophagy machinery bringing an additional level of complexity to the regulation of this biological process in more complex organisms.
    DOI:  https://doi.org/10.1038/s41419-022-05381-9
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