WIPI-Mediated Autophagy and Longevity

Abstract

Autophagy is a lysosomal degradation process for cytoplasmic components, including organelles, membranes, and proteins, and critically secures eukaryotic cellular homeostasis and survival. Moreover, autophagy-related (ATG) genes are considered essential for longevity control in model organisms. Central to the regulatory relationship between autophagy and longevity is the control of insulin/insulin-like growth factor receptor-driven activation of mTOR (mechanistic target of rapamycin), which inhibits WIPI (WD repeat protein interacting with phosphoinositides)-mediated autophagosome formation. Release of the inhibitory mTOR action on autophagy permits the production of PI3P (phosphatidylinositol-3 phosphate), predominantly at the endoplasmic reticulum, to function as an initiation signal for the formation of autophagosomes. WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins. The important role of WIPI proteins in autophagy is highlighted by functional knockout of the WIPI homologues ATG-18 and EPG-6 in Caenorhabditis elegans (C. elegans). Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors. In this review we summarize the role of WIPI proteins and their C. elegans homologues with regard to the molecular basis of aging. As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.

TRAPPC11 functions in autophagy by recruiting ATG2B‐WIPI4/WDR45 to preautophagosomal membranes

“…Autophagosome formation follows a maturation process where proteins function sequentially to produce these organelles. Two such proteins that are thought to associate with isolation membranes are ATG5 and WIPI1 . Thus, we used HeLa cells that express GFP‐tagged versions of these proteins to assess their colocalization with TRAPP III proteins.…”

“…While the extreme amino‐terminus of ATG2 is required for isolation membrane binding in vivo, the interactions that regulate its membrane association are unclear. Because WIPI proteins are recruited to PI3P‐containing membranes, and WIPI4 interacts with ATG2, WIPI4 is thought to recruit ATG2 to such membranes that form after starvation. However, this complex still interacts in vitro with artificial liposomes devoid of PI3P .…”

Longevity and aging. Mechanisms and perspectives

“…Another interesting example concerns the Autophagy-Related Genes (ATG) controlling insulin -insulin receptor-mediated-reactions [20]. Gender-determining genes were also shown to be important mainly in the inheritance of exceptional longevity [21].…”

Sodium butyrate inhibits migration and induces AMPK‐mTOR pathway‐dependent autophagy and ROS‐mediated apoptosis via the miR‐139‐5p/Bmi‐1 axis in human bladder cancer cells

“…Misfolded proteins, damaged mitochondria, and exogenous pathogens, as well as biological material, are wrapped in double‐membrane vesicles that are known as autophagosomes to be delivered for lysosomal degradation. This precise process is executed by autophagy‐related (ATG) proteins . ATG7 has been reported to be a vital regulator of autophagy and plays an irreplaceable role in regular biological processes .…”