Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL.
Luciano. Frederic F; Zhai. Dayong D; Zhu. Xiuwen X; Bailly-Maitre. Beatrice B; Ricci. Jean-Ehrland JE; Satterthwait. Arnold C AC; Reed. John C JC
Key Findings
- Humanin binds directly to the BimEL isoform but not to BimL or BimS
- Binding of Humanin to BimEL prevents BimEL‑induced apoptosis in cell experiments
- Humanin suppresses BimEL‑driven release of mitochondrial death factors (SMAC and cytochrome c) even without Bax
- Humanin blocks BimEL‑induced Bak oligomerization, further inhibiting the death cascade
Practical Outcomes
- Humanin may offer a cellular protective effect that could be attractive for longevity or stress‑resilience strategies, but the research is still at the molecular/cell level. No human dosing, safety, or efficacy data are available yet, so biohackers should wait for clinical studies before adding it to protocols.
Summary
Humanin is a small natural peptide that can block a specific cell‑death protein called BimEL, helping cells survive harmful stress. This adds to its known ability to inhibit another death protein, Bax, showing it works through multiple anti‑apoptotic pathways.
Abstract
Humanin (HN) is a recently identified endogenous peptide that protects cells against cytotoxicity induced by various stimuli. Recently, we showed that HN binds to and inhibits Bax, a proapoptotic Bcl-2 family protein, suggesting a mechanism for HN action. In this study, we identified Bim, a Bcl-2 homology 3-only member of the Bcl-2/Bax family, as an additional HN target protein. Using in vitro protein binding, immunoprecipitation, and coimmunolocalization assays, we demonstrated that HN binds directly to the extra long isoform of Bim (BimEL) but not the long (BimL) or short (BimS) isoforms. HN also protects cells against apoptosis induced by BimEL but not BimL and BimS in gene transfection studies. In contrast, mutants of HN which failed to bind BimEL failed to protect from BimEL-induced cell death. Moreover, HN inhibited BimEL-induced release of SMAC and cytochrome c from mitochondria isolated from bax-/-cells, indicating that HN can suppress BimEL independently of its effect on Bax. Finally, we demonstrate that HN prevents BimEL-induced oligomerization of Bak using isolated mitochondria. Taken together, our results indicate that the inhibition of BimEL may contribute to the antiapoptotic properties of the HN peptide.
Study Information
pubmed
2005
2005-01-20T00:00:00.000Z
10.1074/jbc.m413062200