Figure 6. Tentative model of C9ORF72 function.

1. C9ORF72 in complex with SMCR8 and WDR41 acts as a GDP/GTP exchange factor for RAB39b GTPase, which interacts with the P62 autophagy receptor. Phosphorylation of SMCR8 by TBK1 potentially promotes C9ORF72 GEF activity and enhances autophagy turnover of proteins such as TDP‐43 or Ataxin‐2 with intermediate polyQ size. In the absence of C9ORF72, autophagy clearance of these proteins is reduced and TDP‐43, P62, or Ataxin‐2 with intermediate length of polyQ accumulates into cytoplasmic aggregates.
2. Autophagy receptors such as P62 or OPTN act as hubs to gather Rab GTPases with their GEF effectors and kinase regulators to initiate autophagy precisely at the site of damaged organelles, protein aggregates, or intracellular pathogens.