Journal
CURRENT BIOLOGY
Volume 31, Issue 15, Pages 3440-+Publisher
CELL PRESS
DOI: 10.1016/j.cub.2021.05.052
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Funding
- Funda-cion Ramon Areces Postdoctoral Fellowship
- NIH [K99AG062774]
- George E. Hewitt Foundation for Medical Research
- Royal Thai Government Scholarship from the Development and Promotion of Sci-ence and Technology Talents Project (DPST)
- Glenn Foundation for Medical Research Glenn Award for Research in Biological Mechanisms of Aging [R01AG049483]
- New Scholar in Aging Award from the Lawrence Ellison Foundation
- Baxter Family Foundation [R01 GM117466]
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Autophagy is a conserved cellular process that promotes homeostasis by degrading cytosolic components. The ATG8 protein family interacts with FYCO1 to regulate the directional transport of autophagosomes.
Macroautophagy (hereafter referred to as autophagy) is a conserved process that promotes cellular homeostasis through the degradation of cytosolic components, also known as cargo. During autophagy, cargo is sequestered into double-membrane vesicles called autophagosomes, which are predominantly transported in the retrograde direction to the perinuclear region to fuse with lysosomes, thus ensuring cargo degradation.(1) The mechanisms regulating directional autophagosomal transport remain unclear. The ATG8 family of proteins associates with autophagosome membranes(2) and plays key roles in autophagy, including the movement of autophagosomes. This is achieved via the association of ATG8 with adaptor proteins like FYCO1, involved in the anterograde transport of autophagosomes toward the cell periphery.(1,3-5) We previously reported that phosphorylation of LC3B/ATG8 on threonine 50 (LC3B-T50) by the Hippo kinase STK4/MST1 is required for autophagy through unknown mechanisms.(6) Here, we show that STK4-mediated phosphorylation of LC3BT50 reduces the binding of FYCO1 to LC3B. In turn, impairment of LC3B-T50 phosphorylation decreases starvation-induced perinuclear positioning of autophagosomes as well as their colocalization with lysosomes. Moreover, a significantly higher number of LC3B-T50A-positive autophagosomes undergo aberrant anterograde movement to axonal tips in mammalian neurons and toward the periphery of mammalian cells. Our data support a role of a nutrient-sensitive STK4-LC3B-FYCO1 axis in the regulation of the directional transport of autophagosomes, a key step of the autophagy process, via the post-translational modification of LC3B.
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