TNF induced cleavage of HSP90 by cathepsin D potentiates apoptotic cell death

Area of Science:

• Cellular biology
• Molecular mechanisms of apoptosis
• Signal transduction

Background:

• Apoptosis, or programmed cell death, is crucial for development and disease.
• The extrinsic and intrinsic apoptosis pathways converge at the lysosomal-mitochondrial interface.
• Cathepsin D (CtsD) cleaves Bid to tBid, amplifying apoptosis via mitochondrial outer membrane permeabilization (MOMP).

Purpose of the Study:

• To identify additional Cathepsin D (CtsD) targets involved in death receptor-mediated apoptosis.
• To investigate the role of heat shock protein 90 (HSP90) in apoptosis signaling.

Main Methods:

• Proteomics screening to identify CtsD targets.
• Stimulation of U937 and other cell lines with TNF, FasL, and TRAIL.
• Mutation of HSP90 cleavage sites and overexpression of fragments.
• Pharmacological inhibition of HSP90 using 17AAG.

Main Results:

• Heat shock protein 90 (HSP90) was identified as a Cathepsin D (CtsD) substrate upon death receptor ligation.
• HSP90 cleavage correlated with apoptosis sensitivity across different cell lines.
• Mutating the HSP90 cleavage site partially inhibited apoptosis induction.
• Pharmacological HSP90 inhibition enhanced ligand-mediated apoptosis by promoting Bid cleavage and caspase-9 activation.

Conclusions:

• Heat shock protein 90 (HSP90) plays an anti-apoptotic role in death receptor signaling.
• Cathepsin D (CtsD)-mediated cleavage of HSP90 sensitizes cells to apoptosis.
• HSP90 is a potential therapeutic target for enhancing cancer therapy with death ligands like TNF and TRAIL.