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A ZDHHC5-GOLGA7 Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death

Pin-Joe Ko1, Claire Woodrow1, Michael M Dubreuil2

  • 1Department of Biology, Stanford University, Stanford, CA 94305, USA.

Cell Chemical Biology
|October 22, 2019
PubMed

Insights

A novel small molecule, caspase-independent lethal 56 (CIL56), triggers a unique non-apoptotic cell death pathway. This process involves the ZDHHC5-GOLGA7 protein complex and disrupts protein transport, offering new insights into cell death mechanisms.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Pharmacology

Background:

  • Lethal small molecules are crucial tools for investigating cell death pathways.
  • Understanding novel cell death mechanisms beyond apoptosis is a key area of research.

Purpose of the Study:

  • To characterize the mechanism of cell death induced by the small molecule CIL56.
  • To identify the molecular players involved in CIL56-induced cell death.
  • To define a novel non-apoptotic cell death pathway.

Main Methods:

  • Treatment of cells with CIL56 and structurally related oxime-containing molecules.
  • Biochemical assays to identify protein interactions and enzymatic activity.
  • Cellular transport assays to assess protein trafficking.
  • Genetic manipulation to study the role of ZDHHC5 and GOLGA7.

Main Results:

  • CIL56 induces a form of nonapoptotic cell death distinct from necroptosis and ferroptosis.
  • CIL56-induced cell death requires a functional ZDHHC5-GOLGA7 protein S-acyltransferase complex.
  • The ZDHHC5-GOLGA7 complex localizes to the plasma membrane and is essential for cell survival.
  • CIL56 inhibits anterograde protein transport from the Golgi apparatus.

Conclusions:

  • CIL56 defines an unconventional non-apoptotic cell death pathway regulated by protein S-acylation.
  • The ZDHHC5-GOLGA7 complex plays a critical role in this novel cell death pathway.
  • Disruption of protein transport is a key lethal event in CIL56-induced cell death.
Keywords:
GOLGA7Golgi apparatusPATZDHHC5necrosisnonapoptotic cell deathoximepalmitoylation

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