Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6S10F mutant

Guan Sheng Liu, Hongyan Zhu, Wen Feng Cai, Xiaohong Wang, Min Jiang, Kobina Essandoh, Elizabeth Vafiadaki, Kobra Haghighi, Chi Keung Lam, George Gardner, George Adly, Persoulla Nicolaou, Despina Sanoudou, Qiangrong Liang, Jack Rubinstein, Guo Chang Fan, Evangelia G. Kranias

Research output: Contribution to journalArticlepeer-review

Abstract

HSPB6/Hsp20 (heat shock protein family B [small] member 6) has emerged as a novel cardioprotector against stress-induced injury. We identified a human mutant of HSPB6 (HSPB6S10F) exclusively present in dilated cardiomyopathy (DCM) patients. Cardiac expression of this mutant in mouse hearts resulted in remodeling and dysfunction, which progressed to heart failure and early death. These detrimental effects were associated with reduced interaction of mutant HSPB6S10F with BECN1/Beclin 1, leading to BECN1 ubiquitination and its proteosomal degradation. As a result, autophagy flux was substantially inhibited and apoptosis was increased in HSPB6S10F-mutant hearts. In contrast, overexpression of wild-type HSPB6 (HSPB6 WT) not only increased BECN1 levels, but also competitively suppressed binding of BECN1 to BCL2, resulting in stimulated autophagy. Indeed, preinhibition of autophagy attenuated the cardioprotective effects of HSPB6 WT. Taken together, these findings reveal a new regulatory mechanism of HSPB6 in cell survival through its interaction with BECN1. Furthermore, Ser10 appears to be crucial for the protective effects of HSPB6 and transversion of this amino acid to Phe contributes to cardiomyopathy.

Original languageEnglish
Pages (from-to)80-97
Number of pages18
JournalAutophagy
Volume14
Issue number1
DOIs
Publication statusPublished - 2 Jan 2018
Externally publishedYes

Keywords

  • autophagy
  • BECN1
  • heart failure
  • HSPB6
  • human mutation

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