Mdm l/Snx 13 is a novel ER-endolysosomal interorganelle tethering protein

Although endolysosomal trafficking is well defined, how it is regulated and coordinates with cellular metabolism is unclear. To identify genes governing endolysosomal dynamics, we conducted a global fluorescence-based screen to reveal endomembrane effector genes. Screening implicated Phox (PX) domain-containing protein Mdm 1 in endomembrane dynamics. Surprisingly, we demonstrate that Mdm 1 is a novel interorganelle tethering protein that localizes to endoplasmic reticulum (ER)-vacuole/lysosome membrane contact sites (MCSs). We show that Mdm 1 is ER anchored and contacts the vacuole surface in trans via its lipid-binding PX domain. Strikingly, overexpression of Mdm 1 induced ER vacuole hypertethering, underscoring its role as an interorganelle tether. We also show that Mdm 1 and its paralogue Ydr1 79w-a (named Nvj3 in this study) localize to ER vacuole MCSs independently of established tether Nvi1. Finally, we find that Mdm 1 truncations analogous to neurological disease-associated SNX14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism. Our work suggests that human Mdm 1 homologues may play previously unappreciated roles in interorganelle communication and lipid metabolism.