A Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death

Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferroptosis and classic necrosis. CIL56-induced cell death requires a protein acyltransferase complex comprising the enzyme ZDHHC5 and an accessory subunit, GOLGA7, that is mutually stabilizing and localizes to the plasma membrane. ZDHHC5 activity is not required for CIL56 uptake into the cell, but rather promotes cell death in the context of CIL56 treatment, which inhibits protein secretion from the trans-Golgi apparatus. These results define a novel PAT complex that regulates an unconventional form of nonapoptotic cell death in response to compound treatment.