This is the Rubicon homology domain (RH) characterised at the C-terminal of Rubicon, PLEKHM1 and Pacer, proteins that modulate late steps in autophagy [ PUBMED:32632011 PUBMED:30581147 ]. Rubicon (RUBCN) negatively regulates autophagy and endolysosomal … expand

This is the Rubicon homology domain (RH) characterised at the C-terminal of Rubicon, PLEKHM1 and Pacer, proteins that modulate late steps in autophagy [ PUBMED:32632011 PUBMED:30581147 ]. Rubicon (RUBCN) negatively regulates autophagy and endolysosomal trafficking by inhibiting PI3K complex II (PI3KC3-C2), which impairs autophagosome maturation process. Decrease in autophagy is associated to aging, then suppression of this process by Rubicon has been linked to decreased clearance of alpha-synuclein aggregates in neural tissues, impairment of liver cell homeostasis, and interstitial fibrosis in the kidney. PLEKHM1 is an adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways [ PUBMED:25498145 PUBMED:28325809 ], being involved in the suppression of endocytic transport rather than autophagosome maturation. Mutations in PLEKHM1 causes osteopetrosis [ PUBMED:27291868 ]. On the other hand, Pacer (Protein associated with UVRAG as autophagy enhancer or Rubicon-like) positively regulates autophagy, promoting autophagosome maturation by facilitating the biogenesis of phosphatidylinositol 3-phosphate (PtdIns3P) in late steps of autophagy [ PUBMED:28306502 PUBMED:30704899 ]. It antagonizes RUBCN, thereby stimulating phosphatidylinositol 3-kinase activity of the PI3K/PI3KC3 complex [ PUBMED:28306502 ]. Pacer is involved in neuronal autophagy, whose deficiency leads to impaired autophagy and accumulation of protein aggregates in ALS which correlates with cell death and vulnerability of motoneurons during ALS pathogenesis [ PUBMED:30917850 ].

This domain contains nine conserved cysteines and one conserved histidine, which have been predicted to bind divalent zinc cations, being required for Rubicon and PLEKHM1 to interact with Rab7 [ PUBMED:20943950 PUBMED:33854187 ].