The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics.
Proc Natl Acad Sci U S A
; 118(6)2021 02 09.
Article
em En
| MEDLINE
| ID: mdl-33531362
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes
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Sequência Conservada
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Caenorhabditis elegans
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Proteínas de Caenorhabditis elegans
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Lisossomos
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Proteínas de Membrana
Tipo de estudo:
Etiology_studies
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Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2021
Tipo de documento:
Article