HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis.
Bottom Line: HSPBP1 deficiency in testes strongly reduces the expression of the inducible, antiapoptotic HSP70 family members HSPA1L and HSPA2, the latter of which is essential for synaptonemal complex disassembly during meiosis.We further provide evidence that the cochaperone BAG2 contributes to HSP70 stabilization in tissues other than testes.Our findings reveal that chaperone expression is determined not only by regulated transcription, but also by controlled degradation, with degradation-inhibiting cochaperones exerting essential prosurvival functions.
Affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.Show MeSH
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Mentions: We previously showed that HSPBP1 inhibits the activity of the HSP70-associated ubiquitin ligase CHIP in chaperone/cochaperone complexes (see later discussion of Figure 7; Alberti et al., 2004). In these complexes, CHIP mediates not only the ubiquitylation of bound client proteins, but also that of associated chaperones and cochaperones (Jiang et al., 2001; Alberti et al., 2002; Qian et al., 2006; Arndt et al., 2010). This was shown to trigger the proteasomal degradation of inducible HSPA1A and HSPA1B but not of constitutively expressed HSPA8 (Jiang et al., 2001; Qian et al., 2006). The alterations of the chaperone repertoire observed in testes after HSPBP1 ablation may therefore directly reflect the CHIP-inhibiting activity of the cochaperone. In line with this conclusion, addition of purified HSPBP1 to in vitro ubiquitylation reactions significantly inhibited CHIP-mediated ubiquitylation of HSPA2 and HSPA1L (Figure 6, A–D).
Affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.