Regulation of BECN1-mediated autophagy by HSPB6: Insights from a human HSPB6^S10F mutant

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 (HSPB6) 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 HSPB6 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 HSPB6-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.

A novel human S10F‐Hsp20 mutation induces lethal peripartum cardiomyopathy

“…Upon further investigation, it was discovered that autophagy was significantly depressed in these hearts by 2 months of age because of reduced interaction between Hsp20 and Beclin‐1 and the resultant proteasomal degradation of Beclin‐1. This lack of autophagy led to substantial cardiomyocyte loss and ultimately heart failure in mutant male mice upon ageing . Conversely, the present study highlights a unique gender difference in the S10F‐Hsp20 model, with female hearts exhibiting no changes in Beclin‐1 levels even following multiple pregnancies.…”

“…At the molecular level, transgenic hearts showed a significant reduction in the levels of Bcl‐2/Bax, which may be a major contributing factor to the pro‐apoptotic effects and the development of PPCM. It is important to note that in contrast to males, which exhibited cardiomyocyte loss as a result of diminished autophagy, S10F females showed preservation of autophagy, indicating a separate mechanism is underlying the apoptosis in these hearts.…”

“…We recently reported that male mice with cardiac‐specific overexpression of the S10F‐Hsp20 mutant exhibited cardiac dysfunction by 6 months of age and early lethality (50% dead by 15 months) . Upon further investigation, it was discovered that autophagy was significantly depressed in these hearts by 2 months of age because of reduced interaction between Hsp20 and Beclin‐1 and the resultant proteasomal degradation of Beclin‐1.…”

“…Sections were examined for sarcolemma staining labelled with wheat germ agglutinin (WGA, Invitrogen), according to manufacturer's instruction. Cardiomyocyte cross‐sectional area was measured using ImageJ Software …”

“…We have recently identified a human mutation in the Hsp20 gene, which results in an amino acid change from serine to phenylalanine at position 10 (S10F) . Transgenic (TG) male mice with cardiac overexpression of this mutation presented with impaired autophagy and increased apoptosis at an early age, resulting in cardiac dysfunction, heart failure and reduced survival . These findings prompted us to examine the role of the human S10F‐Hsp20 mutation in females and specifically its effects on cardiac function and remodelling upon pregnancy.…”