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Title of Paper:The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics

Journal:Proceedings of the National Academy of Sciences of the United States of America

Summary: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.

First Author:Shuo Luo

Correspondence Author:Dengke Ma*

All the Authors:Xin Wang,Meirong Bai,Wei Jiang,Zhe Zhang,Yifan Chen

Indexed by:Article

Document Code:7

Document Type:J

Impact Factor:9.41

DOI Number:10.1073/pnas.2011379118

Translation or Not:No

Date of Publication:2021-02

Included Journals:SCI

Release Time:2021-02-09