Death from within: apoptosis and the secretory pathway.

Recent studies have highlighted the importance of the secretory pathway in stress-induced apoptotic signaling. Sensing stress at the endoplasmic reticulum and Golgi might first trigger recovery mechanisms, followed by apoptosis if repair is unsuccessful. Cleavage of endoplasmic-reticulum- or Golgi-resident proteins can signal repair or apoptosis and promote organelle disassembly during apoptosis. Initiation of apoptosis from the secretory pathway requires components of the death machinery localized to these membranes. Extensive trafficking between compartments of the secretory pathway might allow the cell to integrate signals and to determine the proper response to a particular stress.

Caspase-resistant Golgin-160 disrupts apoptosis induced by secretory pathway stress and ligation of death receptors.

Golgin-160 is a coiled-coil protein on the cytoplasmic face of the Golgi complex that is cleaved by caspases during apoptosis. We assessed the sensitivity of cell lines stably expressing wild-type or caspase-resistant golgin-160 to several proapoptotic stimuli. Cells expressing a caspase-resistant mutant of golgin-160 were strikingly resistant to apoptosis induced by ligation of death receptors and by drugs that induce endoplasmic reticulum (ER) stress, including brefeldin-A, dithiothreitol, and thapsigargin. However, both cell lines responded similarly to other proapoptotic stimuli, including staurosporine, anisomycin, and etoposide. The caspase-resistant golgin-160 dominantly prevented cleavage of endogenous golgin-160 after ligation of death receptors or induction of ER stress, which could be explained by a failure of initiator caspase activation. The block in apoptosis in cells expressing caspase-resistant golgin-160 could not be bypassed by expression of potential caspase cleavage fragments of golgin-160, or by drug-induced disassembly of the Golgi complex. Our results suggest that some apoptotic signals (including those initiated by death receptors and ER stress) are sensed and integrated at Golgi membranes and that golgin-160 plays an important role in transduction of these signals.