The conserved autoimmune-disease risk gene regulates lysosome dynamics.

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 () ortholog of TMEM39A, regulates lysosome distribution and accumulation. Elimination of 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 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 or the DYNC1I2 homolog in 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.