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Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced

Vladimir L Gabai1, Katsuhide Mabuchi, Dick D Mosser

  • 1Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Molecular and Cellular Biology
|April 25, 2002
PubMed

Insights

The heat shock protein Hsp72 protects cells from tumor necrosis factor (TNF)-induced apoptosis by inhibiting the Bid-dependent pathway, independent of its chaperone function. This mechanism involves blocking c-jun N-terminal kinase (JNK) activation.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Heat shock proteins (HSPs), like Hsp72, are known to confer cellular protection against various stress-induced damages.
  • Hsp72's role in protecting against tumor necrosis factor (TNF)-induced apoptosis, a key pathway in cell death, requires further mechanistic elucidation.

Purpose of the Study:

  • To investigate the specific mechanism by which Hsp72 protects primary human fibroblasts from TNF-induced apoptosis.
  • To determine the role of Hsp72's chaperone activity in this protective effect.
  • To identify the specific apoptotic pathway targeted by Hsp72.

Main Methods:

  • Utilized primary IMR90 human fibroblasts and fibroblasts from Bid knockout mice.
  • Employed a mutant Hsp72 (Hsp72 Delta EEVD) lacking chaperone function.
  • Assessed apoptosis markers, including Bid activation, cytochrome c release, caspase 3 activation, and poly-ADP-ribose polymerase cleavage.
  • Investigated the involvement of c-jun N-terminal kinase (JNK) pathway.

Main Results:

  • Hsp72 and its chaperone-deficient mutant (Hsp72 Delta EEVD) both inhibited TNF-induced apoptosis, but only wild-type Hsp72 protected against heat shock.
  • Hsp72's protective effect against TNF-induced apoptosis was dependent on Bid, as no additional protection was observed in Bid knockout cells.
  • Both Hsp72 forms inhibited Bid activation, cytochrome c release, caspase 3 activation, and PARP cleavage, and blocked JNK activation by TNF.

Conclusions:

  • Hsp72's chaperone activity is dispensable for suppressing TNF-induced apoptosis but essential for protection against heat shock.
  • Hsp72 specifically targets the Bid-dependent apoptotic pathway, not Bid-independent pathways.
  • Hsp72 inhibits TNF-induced apoptosis by blocking JNK activation, which in turn prevents Bid activation and subsequent downstream apoptotic events.

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