bims-lypmec 2023-07-23 papers

Trends Cell Biol. 2023 Jul 18. pii: S0962-8924(23)00128-9. [Epub ahead of print]

Lysosomal enzyme trafficking: from molecular mechanisms to human diseases.

Thomas Braulke, Jan E Carette, Wilhelm Palm.

Lysosomes degrade and recycle macromolecules that are delivered through the biosynthetic, endocytic, and autophagic routes. Hydrolysis of the different classes of macromolecules is catalyzed by about 70 soluble enzymes that are transported from the Golgi apparatus to lysosomes in a mannose 6-phosphate (M6P)-dependent process. The molecular machinery that generates M6P tags for receptor-mediated targeting of lysosomal enzymes was thought to be understood in detail. However, recent studies on the M6P pathway have identified a previously uncharacterized core component, yielded structural insights in known components, and uncovered functions in various human diseases. Here we review molecular mechanisms of lysosomal enzyme trafficking and discuss its relevance for rare lysosomal disorders, cancer, and viral infection.

Keywords: LYSET; cancer metabolism; lysosomal enzymes; lysosomal storage disorders; mannose 6-phosphate pathway; viral infections

DOI: https://doi.org/10.1016/j.tcb.2023.06.005

Sci Adv. 2023 Jul 21. 9(29): eadh3347

Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.

Wesley Peng, Leonie F Schröder, Pingping Song, Yvette C Wong, Dimitri Krainc.

Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

DOI: https://doi.org/10.1126/sciadv.adh3347

Nat Commun. 2023 07 18. 14(1): 4290

RUFY3 regulates endolysosomes perinuclear positioning, antigen presentation and migration in activated phagocytes.

Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation.

DOI: https://doi.org/10.1038/s41467-023-40062-x

Autophagy. 2023 Jul 21. 1-16

LAMP2A, LAMP2B and LAMP2C: similar structures, divergent roles.

Lei Qiao, Jiayi Hu, Xiaohan Qiu, Chunlin Wang, Jieqiong Peng, Cheng Zhang, Meng Zhang, Huixia Lu, Wenqiang Chen.

LAMP2 (lysosomal associated membrane protein 2) is one of the major protein components of the lysosomal membrane. There currently exist three LAMP2 isoforms, LAMP2A, LAMP2B and LAMP2C, and they vary in distribution and function. LAMP2A serves as a receptor and channel for transporting cytosolic proteins in a process called chaperone-mediated autophagy (CMA). LAMP2B is required for autophagosome-lysosome fusion in cardiomyocytes and is one of the components of exosome membranes. LAMP2C is primarily implicated in a novel type of autophagy in which nucleic acids are taken up into lysosomes for degradation. In this review, the current evidence for the function of each LAMP2 isoform in various pathophysiological processes and human diseases, as well as their possible mechanisms, are comprehensively summarized. We discuss the evolutionary patterns of the three isoforms in vertebrates and provide technical guidance on investigating these isoforms. We are also concerned with the newly arising questions in this particular research area that remain unanswered. Advances in the functions of the three LAMP2 isoforms will uncover new links between lysosomal dysfunction, autophagy and human diseases.Abbreviation: ACSL4: acyl-CoA synthetase long-chain family member 4; AD: Alzheimer disease; Ag: antigens; APP: amyloid beta precursor protein; ATG14: autophagy related 14; AVSF: autophagic vacuoles with unique sarcolemmal features; BBC3/PUMA: BCL2 binding component 3; CCD: C-terminal coiled coil domain; CMA: chaperone-mediated autophagy; CVDs: cardiovascular diseases; DDIT4/REDD1: DNA damage inducible transcript 4; ECs: endothelial cells; ER: endoplasmic reticulum; ESCs: embryonic stem cells; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA/β-glucocerebrosidase: glucosylceramidase beta; GSCs: glioblastoma stem cells; HCC: hepatocellular carcinoma; HD: Huntington disease; HSCs: hematopoietic stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IL3: interleukin 3; IR: ischemia-reperfusion; LAMP2: lysosomal associated membrane protein 2; LDs: lipid droplets; LRRK2: leucine rich repeat kinase 2; MA: macroautophagy; MHC: major histocompatibility complex; MST1: macrophage stimulating 1; NAFLD: nonalcoholic fatty liver disease; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NLRP3: NLR family pyrin domain containing 3; PARK7: Parkinsonism associated deglycase; PD: Parkinson disease; PEA15/PED: proliferation and apoptosis adaptor protein 15; PKM/PKM2: pyruvate kinase M1/2; RA: rheumatoid arthritis; RARA: retinoic acid receptor alpha; RCAN1: regulator of calcineurin 1; RCC: renal cell carcinoma; RDA: RNautophagy and DNautophagy; RNAi: RNA interference; RND3: Rho Family GTPase 3; SG-NOS3/eNOS: deleterious glutathionylated NOS3; SLE: systemic lupus erythematosus; TAMs: tumor-associated macrophages; TME: tumor microenvironment; UCHL1: ubiquitin C-terminal hydrolase L1; VAMP8: vesicle associated membrane protein 8.

Keywords: LAMP2A; LAMP2B; LAMP2C; autophagy; chaperone-mediated autophagy; lysosome

DOI: https://doi.org/10.1080/15548627.2023.2235196

Biochim Biophys Acta Mol Basis Dis. 2023 Jul 14. pii: S0925-4439(23)00178-3. [Epub ahead of print] 166812

Endocytic trafficking of connexins in cancer pathogenesis.

Max Zachrisson Totland, Yasufumi Omori, Vigdis Sørensen, Kushtrim Kryeziu, Trond Aasen, Andreas Brech, Edward Leithe.

Gap junctions are specialized regions of the plasma membrane containing clusters of channels that provide for the diffusion of ions and small molecules between adjacent cells. A fundamental role of gap junctions is to coordinate the functions of cells in tissues. Cancer pathogenesis is usually associated with loss of intercellular communication mediated by gap junctions, which may affect tumor growth and the response to radio- and chemotherapy. Gap junction channels consist of integral membrane proteins termed connexins. In addition to their canonical roles in cell-cell communication, connexins modulate a range of signal transduction pathways via interactions with proteins such as β-catenin, c-Src, and PTEN. Consequently, connexins can regulate cellular processes such as cell growth, migration, and differentiation through both channel-dependent and independent mechanisms. Gap junctions are dynamic plasma membrane entities, and by modulating the rate at which connexins undergo endocytosis and sorting to lysosomes for degradation, cells rapidly adjust the level of gap junctions in response to alterations in the intracellular or extracellular milieu. Current experimental evidence indicates that aberrant trafficking of connexins in the endocytic system is intrinsically involved in mediating the loss of gap junctions during carcinogenesis. This review highlights the role played by the endocytic system in controlling connexin degradation, and consequently gap junction levels, and discusses how dysregulation of these processes contributes to the loss of gap junctions during cancer development. We also discuss the therapeutic implications of aberrant endocytic trafficking of connexins in cancer cells.

Keywords: Intercellular communication; cancer; connexin; endocytosis; gap junction; ubiquitin

DOI: https://doi.org/10.1016/j.bbadis.2023.166812