C9orf72's Interaction with Rab GTPases-Modulation of Membrane Traffic and Autophagy

Abstract

Hexanucleotide repeat expansion in an intron of Chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). While functional haploinsufficiency of C9orf72 resulting from the mutation may play a role in ALS/FTD, the actual cellular role of the protein has been unclear. Recent findings have now shown that C9orf72 physically and functionally interacts with multiple members of the Rab small GTPases family, consequently exerting important influences on cellular membrane traffic and the process of autophagy. Loss of C9orf72 impairs endocytosis in neuronal cell lines, and attenuated autophagosome formation. Interestingly, C9orf72 could influence autophagy both as part of a Guanine nucleotide exchange factor (GEF) complex, or as a Rab effector that facilitates transport of the Unc-51-like Autophagy Activating Kinase 1 (Ulk1) autophagy initiation complex. The cellular function of C9orf72 is discussed in the light of these recent findings.

Keywords: ALS; C9orf72; Rab; autophagy; membrane trafficking.

Figure 1

A schematic diagram illustrating Chromosome 9 open reading frame 72 (C9orf72)’s recently deciphered interaction with various Rab GTPases and its possible roles in membrane traffic and autophagy. C9orf72’s interaction with Rab1A and Rab8A may influence transport along the early and post-Golgi exocytic pathways, respectively (black arrows). Rabs are depicted in red circles with their respective numbers. C9orf72’s functional interactions with the Rabs described in the text are summarized (i to iv): i. C9orf72’s interaction with Rab5, Rab7 and Rab39A may affect endocytic transport (green arrows). ii. Acting as part of the Smith-Magenis Syndrome chromosome region candidate 8 (SMCR8) and WD-40 repeat 41 (WDR41) containing complex, C9orf72 is part of a Guanine nucleotide exchange factor (GEF) complex which activates Rab39B (denoted as a change from green to red). Activated Rab39B’s subsequent engagements of effectors molecules, such as p62, acts in autophagic clearance of ubiquitinated (Ub) substrates. iii. On the other hand, C9orf72 could bridge the ULK1 autophagy initiating complex with Rab1A as an effector of the latter, thus delivering the ULK1 complex to the phagophore. iv. Autophagosomes may have multiple origins, including the membranes of the ER (blue dotted arrow), Golgi apparatus/TGN (black dotted arrow) and the endosomal membranes (green dotted arrow), and C9orf72 may have a role to play in autophagosome generation from these compartments. There is a complex crosstalk between the C9orf72 interacting proteins, for example ULK1 phosphorylates SMCR8, and the autophagy-initiating complex may thus also promote downstream engagement of the autophagy scaffolding protein p62. LE/MVB, late endosome/multivesicular body; EE/RE, early endosome/recycling endosome; Ap, autophagosome.