We are interested in how cellular organelles share information and metabolites such as essential lipids and ions. This is of particular biomedical relevance, as recent work suggests intracellular trafficking of sterols and other dietary lipids is carefully regulated at sites of inter-organelle contact. As such, disruptions in lipid trafficking contribute to an array of genetic and acquired metabolic diseases (eg. Niemann Pick Type C, obesity, and heart disease).
Recently, we identified a new protein family that plays critical roles in ER-endolysosomal cross-talk (see Henne et al, JCB, 2015). These proteins all feature a poorly characterized PX-Associated (PXA domain) and thus we name them the PXA domain-containing family.
Yeast encode two PXA domain-containing proteins: Mdm1 and Nvj3. Both localize to the contact site between the ER and vacuole (the yeast lysosome). Intriguingly, modulation of Mdm1 expression levels governs the degree of ER-vacuole contact, underscoring the ability of this protein to act as an inter-organelle tether in yeast.
PXA domain-containing proteins are highly conserved in metazoans, and numerous orthologs are linked to diseases. Fruit flies encode one homolog named Snazurus (Snz). Surprisingly, loss of SNZ is associated with substancial lifespan extension, suggesting that PXA domain-containing proteins govern organismal aging (Suh, 2008). Four human homologs of Mdm1 are members of the Sorting Nexin (SNX) protein family, and have been linked to pediatric cerebellar ataxia and intellectual disability (Thomas, 2014; Akizu, 2015). Current studies are now focused on revealing the biological role(s) of PXA domain-containing in organismal metabolism and disease.