Inhibition of early-acting autophagy genes inC. elegansneurons improves protein homeostasis, promotes exopher production, and extends lifespan via the ATG-16.2 WD40 domain

Abstract

While autophagy is key to maintain cellular homeostasis, tissue-specific roles of individual autophagy genes are less understood. To study neuronal autophagy in vivo, we inhibited autophagy genes specifically in C. elegans neurons, and unexpectedly found that knockdown of early-acting autophagy genes, i.e., involved in formation of the autophagosome, except for atg-16.2, decreased PolyQ aggregates and increased lifespan, albeit independently of the degradation of autophagosomal cargo. Neuronal aggregates can be secreted from neurons via vesicles called exophers, and we found that neuronal inhibition of early-acting autophagy genes atg-7 and lgg-1/Atg8, but not atg-16.2 increased exopher formation. Moreover, atg-16.2 mutants were unable to form exophers, and atg-16.2 was required for the effects of early autophagy gene reduction on neuronal PolyQ aggregation, exopher formation, and lifespan. Notably, neuronal expression of full-length ATG-16.2 but not ATG-16.2 without a functional WD40 domain, important for non-canonical functions of ATG16L1 in mammalian cells, restored these phenotypes. Collectively, we discovered a specific role for C. elegans ATG-16.2 and its WD40 domain in exopher biogenesis, neuronal proteostasis, and lifespan determination, highlighting a possible role for non-canonical autophagy functions in both exopher formation and in aging.

Non-apoptotic role of EGL-1 in exopher production and neuronal health inCaenorhabditis elegans

“…Intermediate filaments that associate with aggresomes are required cellautonomously for exopher production [33] . Additionally, the autophagy protein ATG-16.2 has been found to promote exopher production cell autonomously [34] . Complementing these findings in stress-response pathways, we discovered that the apoptosis trigger in C. elegans, the BH3-only protein EGL-1, has a non-apoptotic function in promoting exopher production cell-autonomously.…”

Mechanical force of uterine occupation enables large vesicle extrusion from proteostressed maternal neurons

“…We speculate that young adult physiology might be temporally tweaked such that some tissues have optimized capacity to manage/degrade large aggregates and organelles at an early adult developmental “clean up” time, possibly analogous to how a town service for bulky oversized garbage pick-up might be limited to particular times during the year. As exopher production appears generally beneficial for neuronal function and survival 3,77 , the early life extrusion phase appears a positive feature of reproductive life. More broadly, proteome “clean up” phases may be programmed as key steps at specific transitions during development and homeostasis, for example, as occurs in the temporal lysosome activation that clears aggregate debris in C. elegans maturing oocytes 78 or in the maturation of mouse adult neuronal stem cells via vimentin-dependent proteaseome activity during quiescence exit 79 .…”