Abstract

Transport protein particle complex component 11 (TRAPPC11) is a subunit of TRAPP III, a protein complex which is involved in membrane traffic, autophagy and maintenance of Golgi structure. The mechanisms by which it functions in these processes are not fully understood. Mutations in human TRAPPC11 have been linked to a wide spectrum of phenotypes including developmental delays, muscular dystrophies, intellectual disabilities, dystroglycanopathies and fatty liver. Here, we show that TRAPPC11 has a role upstream of autophagosome formation in macroautophagy. This contrasts with other TRAPP III proteins that function earlier (TRAPPC8) or later (TRAPPC12) than TRAPPC11 in the pathway. Upon TRAPPC11 depletion, LC3-positive membranes fail to become sealed autophagosomes and are not cleared during starvation conditions. ATG2B and its binding partner WIPI4/WDR45 are thought to be TRAPPC11 interactors, and TRAPPC11 depletion phenocopies the one of either ATG2 or WIPI4, which act in isolation membrane expansion. In the absence of TRAPPC11, recruitment of both these proteins to membranes is defective and fibroblasts from an individual with an altered carboxy-terminus of TRAPPC11 failed to recruit ATG2B-WIPI4, suggesting that this interaction is physiologically relevant. We propose a model whereby the TRAPP III complex coordinates growth and expansion of the isolation membrane through multiple interactions.

TRAPPC11 can also function independent of the complex in the formation of lipid-linked oligosaccharides in N-glycosylation, so further research is needed to tease apart the roles of TRAPPC11 independently and within the complex. Collectively, all these dysregulated functions could potentially explain the spectrum of phenotypes seen in individuals having variants of TRAPPC11. The region around the highly-conserved Gly980 appears to be critical for membrane trafficking and N-linked glycosylation, causing the muscular weakness phenotype, whereas the extreme carboxy-terminus seems to be involved in autophagy, being linked to some of the same neurological phenotypes shared with TRAPPC12 variants.