Nandi et al. describe how a caspase and a kinase combine to regulate the levels of a protein that stimulates autophagy.

During autophagy, double-membraned autophagosomes engulf cytoplasmic material and deliver it to lysosomes for degradation. This process is drastically up-regulated in starving cells that need to recycle basic nutrients in order to survive. But even well-fed cells use low levels of autophagy to rid themselves of unwanted components such as misfolded proteins or damaged organelles. Autophagy is blocked in the absence of a protein called Acinus and hyperactivated in flies overexpressing this protein. How Acinus levels are regulated in vivo is unclear, however, although it is known that the mammalian protein is a substrate for the protease caspase-3 and the kinase AKT.

Nandi et al. discovered that, in flies, Acinus is cleaved by the caspase Dcp-1. Mutating the cleavage site or knocking out Dcp-1 increased Acinus protein levels and enhanced autophagy even in well-fed flies. Acinus cleavage was inhibited by AKT-mediated phosphorylation. Mutating the AKT phosphorylation sites to phosphomimetic aspartate residues stabilized Acinus and increased the levels of autophagy in fly tissues.

Flies expressing cleavage-resistant forms of Acinus lived longer than wild-type animals, probably due to the protective effects of enhanced autophagy. Indeed, expression of non-cleavable Acinus mutants partially protected flies from the neurodegeneration induced by aggregation-prone Huntingtin protein. Senior author Helmut Krämer now wants to investigate how Acinus stimulates autophagy, as the protein’s biochemical function is currently unclear.


, et al
J. Cell Biol.

Author notes

Text by Ben Short