bims-lymeca 2023-10-29 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2023–10–29
nine papers selected by
Harilaos Filippakis, University of New England

Nutrient-regulated control of lysosome function by signaling lipid conversion.
L-Type Amino Acid Transporter 1 (LAT1) Promotes PMA-Induced Cell Migration through mTORC2 Activation at the Lysosome.
ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage.
Inducin Triggers LC3-Lipidation and ESCRT-Mediated Lysosomal Membrane Repair.
Iridoid glycosides from Morinda officinalis induce lysosomal biogenesis and promote autophagic flux to attenuate oxidative stress.
Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.
A candidate prognostic biomarker: TFEB inhibits tumor progression via elevating CDKN1A in bladder cancer.
Cathepsin L-mediated EGFR cleavage affects intracellular signalling pathways in cancer.
Bladder cancer.

Cell. 2023 Oct 18. pii: S0092-8674(23)01081-4. [Epub ahead of print]

Nutrient-regulated control of lysosome function by signaling lipid conversion.

Michael Ebner, Dmytro Puchkov, Orestes López-Ortega, Pathma Muthukottiappan, Yanwei Su, Christopher Schmied, Silke Zillmann, Iryna Nikonenko, Jochen Koddebusch, Gillian L Dornan, Max T Lucht, Vonda Koka, Wonyul Jang, Philipp Alexander Koch, Alexander Wallroth, Martin Lehmann, Britta Brügger, Mario Pende, Dominic Winter, Volker Haucke.

  Lysosomes serve dual antagonistic functions in cells by mediating anabolic growth signaling and the catabolic turnover of macromolecules. How these janus-faced activities are regulated in response to cellular nutrient status is poorly understood. We show here that lysosome morphology and function are reversibly controlled by a nutrient-regulated signaling lipid switch that triggers the conversion between peripheral motile mTOR complex 1 (mTORC1) signaling-active and static mTORC1-inactive degradative lysosomes clustered at the cell center. Starvation-triggered relocalization of phosphatidylinositol 4-phosphate (PI(4)P)-metabolizing enzymes reshapes the lysosomal surface proteome to facilitate lysosomal proteolysis and to repress mTORC1 signaling. Concomitantly, lysosomal phosphatidylinositol 3-phosphate (PI(3)P), which marks motile signaling-active lysosomes in the cell periphery, is erased. Interference with this PI(3)P/PI(4)P lipid switch module impairs the adaptive response of cells to altering nutrient supply. Our data unravel a key function for lysosomal phosphoinositide metabolism in rewiring organellar membrane dynamics in response to cellular nutrient status.

Keywords:  catabolism; functional proteomics; live correlative light and electron microscopy; lysosomes; mTOR; myotubularin; nutrient signaling; nutrients; phosphoinositides

DOI:  https://doi.org/10.1016/j.cell.2023.09.027
Cells. 2023 Oct 23. pii: 2504. [Epub ahead of print]12(20):

L-Type Amino Acid Transporter 1 (LAT1) Promotes PMA-Induced Cell Migration through mTORC2 Activation at the Lysosome.

Kun Tae, Sun-Jick Kim, Sang-Woo Cho, Hoyeon Lee, Hyo-Sun Cha, Cheol-Yong Choi.

  The mTOR signaling pathway integrates signaling inputs from nutrients, including glucose and amino acids, which are precisely regulated by transporters depending on nutrient levels. The L-type amino acid transporter 1 (LAT1) affects the activity of mTORC1 through upstream regulators that sense intracellular amino acid levels. While mTORC1 activation by LAT1 has been thoroughly investigated in cultured cells, the effects of LAT1 expression on the activity of mTORC2 has scarcely been studied. Here, we provide evidence that LAT1 recruits and activates mTORC2 on the lysosome for PMA-induced cell migration. LAT1 is translocated to the lysosomes in cells treated with PMA in a dose- and time-dependent manner. Lysosomal LAT1 interacted with mTORC2 through a direct interaction with Rictor, leading to the lysosomal localization of mTORC2. Furthermore, the depletion of LAT1 reduced PMA-induced cell migration in a wound-healing assay. Consistent with these results, the LAT1 N3KR mutant, which is defective in PMA-induced endocytosis and lysosomal localization, did not induce mTORC2 recruitment to the lysosome, with the activation of mTORC2 determined via Akt phosphorylation or the LAT1-mediated promotion of cell migration. Taken together, lysosomal LAT1 recruits and activates the mTORC2 complex and downstream Akt for PMA-mediated cell migration. These results provide insights into the development of therapeutic drugs targeting the LAT1 amino acid transporter to block metastasis, as well as disease progression in various types of cancer.

Keywords:  LAT1; PMA; cell migration; mTORC2

DOI:  https://doi.org/10.3390/cells12202504
Autophagy. 2023 Oct 23. 1-2

ATG12-ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage.

Dale P Corkery, Yao-Wen Wu.

  ATG16L1 is an essential component of the Atg8-family protein conjugation machinery, providing membrane targeting for the ATG12-ATG5 conjugate. Recently, we identified an alternative E3-like complex that functions independently of ATG16L1. This complex utilizes the autophagosome-lysosome tethering factor TECPR1 for membrane targeting. TECPR1 is recruited to damaged lysosomal membranes via a direct interaction with sphingomyelin. At the damaged membrane, TECPR1 assembles into an E3-like complex with ATG12-ATG5 to regulate unconventional LC3 lipidation and promote efficient lysosomal repair.

Keywords:  ESCRT; TECPR1; lysophagy; lysosome; membrane repair

DOI:  https://doi.org/10.1080/15548627.2023.2267414
Chembiochem. 2023 Oct 23. e202300579

Inducin Triggers LC3-Lipidation and ESCRT-Mediated Lysosomal Membrane Repair.

Dale Corkery, Andrei Ursu, Belén Lucas, Michael Grigalunas, Simon Kriegler, Rosario Oliva, Robert Dec, Sandra Koska, Axel Pahl, Sonja Sievers, Slava Ziegler, Roland Winter, Yaowen Wu, Herbert Waldmann.

  Lipidation of the LC3 protein has frequently been employed as a marker of autophagy. However, LC3-lipidation is also triggered by stimuli not related to canonical autophagy. Therefore, characterization of the driving parameters for LC3 lipidation is crucial to understanding the biological roles of LC3. We identified a pseudo-natural product, termed Inducin, that increases LC3 lipidation independently of canonical autophagy, impairs lysosomal function and rapidly recruits Galectin 3 to lysosomes. Inducin treatment promotes Endosomal Sorting Complex Required for Transport (ESCRT)-dependent membrane repair and transcription factor EB (TFEB)-dependent lysosome biogenesis ultimately leading to cell death.

Keywords:  Biological activity; Endolysosomal membrane damage; LC3 lipidation; Lysosomal membrane permeabilization; Small molecule

DOI:  https://doi.org/10.1002/cbic.202300579
J Asian Nat Prod Res. 2023 Oct 27. 1-13

Iridoid glycosides from Morinda officinalis induce lysosomal biogenesis and promote autophagic flux to attenuate oxidative stress.

Yin-Yuan Wang, Jian-Cheng Ni, Yue-Qin Zhao, Xu Yang, Zhen-Peng Niu, Xing-Zhi Yang, Xian-Xiang Dong, Yu-Han Zhao, Xiao-Jiang Hao, Xiao Ding.

  Morinda officinalis is a traditional Chinese tonic herb, and have been used in the treatment of multiple diseases. Here, three iridoid glycosides isolated from M. officinalis were evaluated for their roles in the autophagy-lysosomal pathway. All three iridoid glycosides could induce TFEB/TFE3-mediated lysosomal biogenesis and trigger autophagy. Interestingly, they promoted the nuclear import of TFEB/TFE3 without affecting their nuclear export, suggesting their role in the maintenance of lysosomal homeostasis. The results from this study shed light on the identification of autophagy activators from M. officinalis and provide a basis for developing them in the treatment of oxidative stress-involved diseases.

Keywords:  Iridoid glycosides; Morinda officinalis; TFEB/TFE3; antioxidant activity; lysosomal biogenesis

DOI:  https://doi.org/10.1080/10286020.2023.2269370
Elife. 2023 Oct 24. pii: e87255. [Epub ahead of print]12

Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.

Xiang Wang, Vitaliy V Bondar, Oliver B Davis, Michael T Maloney, Maayan Agam, Marcus Y Chin, Audrey Cheuk-Nga Ho, Rajarshi Ghosh, Dara E Leto, David Joy, Meredith E K Calvert, Joseph W Lewcock, Gilbert Di Paolo, Robert G Thorne, Zachary K Sweeney, Anastasia G Henry.

  Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson's disease (PD) and Crohn's disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.

Keywords:  cell biology; human

DOI:  https://doi.org/10.7554/eLife.87255
Int Immunopharmacol. 2023 Oct 25. pii: S1567-5769(23)01341-3. [Epub ahead of print]125(Pt A): 111016

A candidate prognostic biomarker: TFEB inhibits tumor progression via elevating CDKN1A in bladder cancer.

Minghao Yue, Zhe Yang, Jiabin Sun, Zan Liu.

  Bladder cancer(BC) is among the most prevalent malignancies in the world, with 549,393 new cases documented in 2018, and most BC patients have a poor prognosis. Transcription factor EB (TFEB) is considered a crucial controller of lysosomal-associated diseases, but a growing number of research in recent years have reported that TFEB plays other functions in tumors independent of lysosomal autophagy. In this study, we aimed to assess whether TFEB is a biomarker for BC and a molecular target for BC therapy. TFEB was lowly expressed in BC tissues relative to paracancerous tissues, and its elevated expression was strongly associated to a better prognosis for BC patients. TFEB overexpression markedly suppressed cell proliferation, limited cell migration, and accelerated apoptosis. Tumor growth in vivo was also suppressed. Mechanistically, we found that TFEB promoted CDKN1A expression by binding to the upstream progenitor of the CDKN1A promoter, which was also dependent on p53. Finally, Immune cell infiltration in BC tissues, PDL-1 expression, and Single-cell RNA sequencing data revealed immunotherapy may have a positive correlation with TFEB expression. Our study identifies that TFEB regulates CDKN1A in BC and has a positive prognostic value, while its expression is also positively correlated with immune cell infiltration. Therefore, TFEB may represent a recent therapeutic target for BC.

Keywords:  Bladder cancer; CDKN1A; P53; Single-cell; TFEB

DOI:  https://doi.org/10.1016/j.intimp.2023.111016
Biol Chem. 2023 Oct 30.

Cathepsin L-mediated EGFR cleavage affects intracellular signalling pathways in cancer.

Marija Grozdanić, Barbara Sobotič, Monika Biasizzo, Tilen Sever, Robert Vidmar, Matej Vizovišek, Boris Turk, Marko Fonović.

  Proteolytic activity in the tumour microenvironment is an important factor in cancer development since it can also affect intracellular signalling pathways via positive feedback loops that result in either increased tumour growth or resistance to anticancer mechanisms. In this study, we demonstrated extracellular cathepsin L-mediated cleavage of epidermal growth factor receptor (EGFR) and identified the cleavage site in the extracellular domain after R224. To further evaluate the relevance of this cleavage, we cloned and expressed a truncated version of EGFR, starting at G225, in HeLa cells. We confirmed the constitutive activation of the truncated protein in the absence of ligand binding and determined possible changes in intracellular signalling. Furthermore, we determined the effect of truncated EGFR protein expression on HeLa cell viability and response to the EGFR inhibitors, tyrosine kinase inhibitor (TKI) erlotinib and monoclonal antibody (mAb) cetuximab. Our data reveal the nuclear localization and phosphorylation of EGFR and signal trancducer and activator of transcription 3 (STAT3) in cells that express the truncated EGFR protein and suggest that these phenomena cause resistance to EGFR inhibitors.

Keywords:  EGFR; cancer; cathepsin L; cysteine cathepsin; extracellular cleavage; resistance to TKIs

DOI:  https://doi.org/10.1515/hsz-2023-0213
Nat Rev Dis Primers. 2023 Oct 26. 9(1): 59

Bladder cancer.

DOI: https://doi.org/10.1038/s41572-023-00475-w