The Rab7 effector WDR91 promotes autophagy-lysosome degradation in neurons by regulating lysosome fusion

Abstract

The effectors of the Rab7 small GTPase play multiple roles in Rab7-dependent endosome-lysosome and autophagy-lysosome pathways. However, it is largely unknown how distinct Rab7 effectors coordinate to maintain the homeostasis of late endosomes and lysosomes to ensure appropriate endolysosomal and autolysosomal degradation. Here we report that WDR91, a Rab7 effector required for early-to-late endosome conversion, is essential for lysosome function and homeostasis. Mice lacking Wdr91 specifically in the central nervous system exhibited behavioral defects and marked neuronal loss in the cerebral and cerebellar cortices. At the cellular level, WDR91 deficiency causes PtdIns3P-independent enlargement and dysfunction of lysosomes, leading to accumulation of autophagic cargoes in mouse neurons. WDR91 competes with the VPS41 subunit of the HOPS complex, another Rab7 effector, for binding to Rab7, thereby facilitating Rab7-dependent lysosome fusion in a controlled manner. WDR91 thus maintains an appropriate level of lysosome fusion to guard the normal function and survival of neurons.

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

“…Whereas EEs and LEs were detected throughout the length of dendrites, mature lysosomes positive for LAMP1 and cathepsins B and D (CTSB/D) were largely confined to the cell body and proximal dendritic regions ( Yap et al, 2018 ). Consistently, the Rab7 effector WDR91 involved in early-to-late endosome conversion is required for endosome maturation in neurites, which is essential for dendrite growth and neuronal lysosome function ( Liu et al, 2017 ; Xing et al, 2021 ). Similarly, impaired retrograde transport of endolysosomal organelles in axons caused an accumulation of immature lysosomes in neurons, leading to decreased proteolytic capability ( Cai et al, 2010 ; Gowrishankar et al, 2017 ; Gowrishankar et al, 2015 ; Lee et al, 2011 ).…”

Who’s in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond

“…In yeast, the Rab7-homologue Ypt7 mediates HOPS-dependent fusion of autophagosomes with vacuoles ( Gao et al, 2018a ). In metazoan cells, Rab7 and its effectors PLEKHM1 and WDR91 are required for autolysosome/amphisome-lysosome fusion, yet Rab7 does not seem to directly bind HOPS during fusion of autophagosomes with lysosomes ( Xing et al, 2021 ; McEwan et al, 2015 ; Gutierrez et al, 2004 ; Kuchitsu and Fukuda, 2018 ).…”

A genome-wide CRISPR interference screen using an engineered trafficking biosensor reveals a role for RME-8 in opioid receptor regulation

“…Liu et al 2018; Hermle et al 2018; Guillen et al 2020; Lacey et al 2022; Fujibayashi et al 2008; K. Liu et al 2017; Xing et al 2021). Two sgRNAs per gene were independently transduced into HEK293-FLP cells stably expressing UBC:DOR-APEX2 and dCas9-KRAB and compared to a NTC sgRNA in agonist-stimulated trafficking of the DOR.…”