Dissection Of The Role Of GAPDH In Autophagy

Autophagy, a major degradation/recycling system in eukaryotic cells, is a quality control mechanism for the maintainance of cell homeostasis. Aberrant autophagy has been associated with a variety of human diseases including neurodegeneration and tumorigenesis. Despite recent advances in understanding the process of autophagy, the molecular mechanisms of autophagy program remain enigmatic.Recent studies have identified the nuclear NAD+-dependent deacetylase sirtuin 1(Sirtl) as an important regulator of autopahgy. However, little is known about the activation of Sirtl during autophagy. In this study, we find that the cytoplasmic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) translocated into the nucleus upon autophagy induction by cell starvation or Rapamycin treatment. Either depletion of GAPDH or pharmaceutical inhibition of GAPDH nuclear entry prevented starvation-induced autophagy. Forced expression of a nuclear-localized. GAPDH enhanced both constitutive and adaptive autophagy. We further demonstrate that AMP-activated protein kinase (AMPK) controlled the translocation of GAPDH during autophagy.Mechanism analyses demonstrated that the nuclear GAPDH moved from the cytoplasm interacted with and activated Sirtl, which is primarily in the nucleus. Depletion of Sirtl or Sirtl inhibitor dramatically suppressed nuclear GAPDH-evoked autophagy. We further show that GAPDH-Sirtl interaction released Sirtl from DBC1, a protein that binds with Sirtl and inhibits Sirtl activity.Taking together, our findings have identified GAPDH as a new regulator for autophagy. By translocating from the cytoplasm to the nucleus in response to autophagic signaling, GAPDH activates Sirtl in the nucleus, thereby playing a crucial role in autophagy.