A Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death

Death by Retrograde Transport: Avoiding the Apoptosis Default

“…The mechanism suggested by Ko et al (2019) appears likely (Figure 1), although with a caveat. The function of ZDHCC5 requires its auto-palmitoylation, which can explain the requirement for fatty acid synthesis, and it remains possible that some other function of ZDHCC5, other than retrograde transport, might be necessary for the lethal effects of CIL56.…”

“…Examples of the latter include ferroptosis, where mechanisms to prevent lethal lipid peroxidation are de-railed, and parthanatos, where the excessive engagement of DNA repair pathways (i.e., Poly-ADP ribose polymerase) depletes essential energy stores (Green, 2018). In this issue, Dixon and colleagues (Ko et al, 2019) describe a chemical agent, CIL56, that preferentially kills many tumor cell lines while sparing normal cells, by sabotaging a transport process, leading to death of the cell via a modality that appears to be distinct from any so far described. Inhibitors of apoptosis, necroptosis, pyroptosis, or ferroptosis had no effect on cell death induced by CIL56.…”

“…CIL56 was identified in a screen for compounds capable of preferentially killing tumor lines (Dixon et al, 2015). The authors now find that of 94 cancer lines examined, CIL56 potently kills most hematologic cancer lines, as well as many others (although, notably, not those of liver or muscle origin), while completely sparing normal peripheral blood mononuclear cells (PBMCs) (Ko et al, 2019). Consistent with their earlier findings (Dixon et al, 2015), and using an siRNA screen, they have now confirmed that toxicity of CIL56 depends on fatty acid synthesis, as silencing or pharmacologic inhibition of fatty acid synthase (Fasn), acetyl-CoA carboxylase-1 (ACC1), or long-chain-fattyacid-CoA ligase-3 (ACSL3) all prevent killing by this agent.…”

“…Unlike most PATs, ZDHHC5 localizes to the plasma membrane, where it is thought to function in retrograde transport of membranes to the Golgi (Breusegem and Seaman, 2014). Dixon and colleagues found that CIL56 inhibits anterograde transport from the Golgi, leading to physical expansion of this organelle (Ko et al, 2019). In the presence of CIL56, and in a ZDHHC5-and Golga7-dependent manner, cells accumulated intracellular vesicles containing membrane proteins, although whether these were meant to go to or from the Golgi is not clear.…”

“…While Dixon and colleagues observed no change in mitochondrial membrane potential that occurs upon mPTP, they did note changes in mitochondrial morphology. ZDHHC5 has also been implicated in the uptake of free fatty acids by the CD36 scavenger receptor, although this process is also dependent on ZDHHC4 (Wang et al, 2019), which was not identified in the siRNA screen of Ko et al (2019).…”