The conserved autoimmune-disease risk gene <i>TMEM39A</i> regulates lysosome dynamics.

Abstract

<i>TMEM39A</i> 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 <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) ortholog of TMEM39A, regulates lysosome distribution and accumulation. Elimination of <i>tmem-39</i> 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 <i>TMEM39A</i> 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 <i>tmem-39</i> or the DYNC1I2 homolog in <i>C. elegans</i> 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.