The Dynein Adaptor RILP Controls Neuronal Autophagosome Biogenesis, Transport, and Clearance

Abstract

Autophagy plays critical roles in neurodegeneration and development, but how this pathway is organized and regulated in neurons remains poorly understood. Here, we find that the dynein adaptor RILP is essential for retrograde transport of neuronal autophagosomes, and surprisingly, their biogenesis as well. We find that induction of autophagy by mTOR inhibition specifically upregulates RILP expression and its localization to autophagosomes. RILP depletion or mutations in its LC3-binding LIR motifs strongly decrease autophagosome numbers suggesting an unexpected RILP role in autophagosome biogenesis. We find that RILP also interacts with ATG5 on isolation membranes, precluding premature dynein recruitment and autophagosome transport. RILP inhibition impedes autophagic turnover and causes p62/sequestosome-1 aggregation. Together, our results identify an mTOR-responsive neuronal autophagy pathway, wherein RILP integrates the processes of autophagosome biogenesis and retrograde transport to control autophagic turnover. This pathway has important implications for understanding how autophagy contributes to neuronal function, development, and disease.

Keywords: RILP; autophagosome biogenesis; dynein; isolation membranes; mTOR regulation; neuronal autophagy; retrograde transport; sequestosome-1/p62.