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The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Feb 09; Vol. 118 (6). - Publication Year :
- 2021
-
Abstract
- TMEM39A encodes an evolutionarily conserved transmembrane protein and carries single-nucleotide polymorphisms associated with increased risk of major human autoimmune diseases, including multiple sclerosis. The exact cellular function of TMEM39A remains not well understood. Here, we report that TMEM-39, the sole Caenorhabditis elegans ( C. elegans ) ortholog of TMEM39A, regulates lysosome distribution and accumulation. Elimination of tmem-39 leads to lysosome tubularization and reduced lysosome mobility, as well as accumulation of the lysosome-associated membrane protein LMP-1. In mammalian cells, loss of TMEM39A leads to redistribution of lysosomes from the perinuclear region to cell periphery. Mechanistically, TMEM39A interacts with the dynein intermediate light chain DYNC1I2 to maintain proper lysosome distribution. Deficiency of tmem-39 or the DYNC1I2 homolog in C. elegans impairs mTOR signaling and activates the downstream TFEB-like transcription factor HLH-30. We propose evolutionarily conserved roles of TMEM39 family proteins in regulating lysosome distribution and lysosome-associated signaling, dysfunction of which in humans may underlie aspects of autoimmune diseases.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- Animals
Caenorhabditis elegans metabolism
Caenorhabditis elegans Proteins chemistry
Caenorhabditis elegans Proteins metabolism
Dyneins metabolism
Genetic Predisposition to Disease
Membrane Proteins chemistry
Membrane Proteins metabolism
Mutation genetics
Neurons metabolism
Risk Factors
Signal Transduction
Subcutaneous Tissue metabolism
TOR Serine-Threonine Kinases metabolism
Autoimmune Diseases genetics
Caenorhabditis elegans genetics
Caenorhabditis elegans Proteins genetics
Conserved Sequence genetics
Lysosomes metabolism
Membrane Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 33531362
- Full Text :
- https://doi.org/10.1073/pnas.2011379118