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HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis.

Rogon C, Ulbricht A, Hesse M, Alberti S, Vijayaraj P, Best D, Adams IR, Magin TM, Fleischmann BK, Höhfeld J - Mol. Biol. Cell (2014)

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.

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Affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.

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Role of HSPBP1 and BAG2 as regulators of CHIP-mediated degradation. (A)                            Schematic presentation of the HSP70/cochaperone network that regulates                            CHIP-mediated protein degradation. CHIP binds to the carboxy terminus of                            HSP70 and ubiquitylates the chaperone and bound client proteins in                            conjunction with ubiquitin-conjugating enzymes of the UBCH4/5 family.                            Targeting to the proteasome is assisted by the cochaperone BAG1, whereas                            binding of BAG3 to the chaperone/CHIP complex induces the lysosomal                            degradation of the client. HSPBP1 and BAG2 inhibit the ubiquitin ligase                            activity of CHIP in the assembled chaperone complex and thereby                            facilitate the folding of the client. (B) Schematic presentation of the                            CHIP/HSPBP1/BAG2 cochaperone network that balances the expression of                            inducible HSP70 chaperones at the posttranslational level. CHIP is able                            to mediate the ubiquitylation of inducible HSP70s and induces their                            proteasomal degradation. Association of HSPBP1 or BAG2 with the                            HSP70/CHIP complex results in an inhibition of CHIP activity, leading to                            stabilization of inducible HSP70s. *Present study; (1) Jiang et al. (2001),                            (2) Qian et al.                                (2006), (3) Sasaki                                    et al. (2008).
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Figure 7: Role of HSPBP1 and BAG2 as regulators of CHIP-mediated degradation. (A) Schematic presentation of the HSP70/cochaperone network that regulates CHIP-mediated protein degradation. CHIP binds to the carboxy terminus of HSP70 and ubiquitylates the chaperone and bound client proteins in conjunction with ubiquitin-conjugating enzymes of the UBCH4/5 family. Targeting to the proteasome is assisted by the cochaperone BAG1, whereas binding of BAG3 to the chaperone/CHIP complex induces the lysosomal degradation of the client. HSPBP1 and BAG2 inhibit the ubiquitin ligase activity of CHIP in the assembled chaperone complex and thereby facilitate the folding of the client. (B) Schematic presentation of the CHIP/HSPBP1/BAG2 cochaperone network that balances the expression of inducible HSP70 chaperones at the posttranslational level. CHIP is able to mediate the ubiquitylation of inducible HSP70s and induces their proteasomal degradation. Association of HSPBP1 or BAG2 with the HSP70/CHIP complex results in an inhibition of CHIP activity, leading to stabilization of inducible HSP70s. *Present study; (1) Jiang et al. (2001), (2) Qian et al. (2006), (3) Sasaki et al. (2008).

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).


HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis.

Rogon C, Ulbricht A, Hesse M, Alberti S, Vijayaraj P, Best D, Adams IR, Magin TM, Fleischmann BK, Höhfeld J - Mol. Biol. Cell (2014)

Role of HSPBP1 and BAG2 as regulators of CHIP-mediated degradation. (A)                            Schematic presentation of the HSP70/cochaperone network that regulates                            CHIP-mediated protein degradation. CHIP binds to the carboxy terminus of                            HSP70 and ubiquitylates the chaperone and bound client proteins in                            conjunction with ubiquitin-conjugating enzymes of the UBCH4/5 family.                            Targeting to the proteasome is assisted by the cochaperone BAG1, whereas                            binding of BAG3 to the chaperone/CHIP complex induces the lysosomal                            degradation of the client. HSPBP1 and BAG2 inhibit the ubiquitin ligase                            activity of CHIP in the assembled chaperone complex and thereby                            facilitate the folding of the client. (B) Schematic presentation of the                            CHIP/HSPBP1/BAG2 cochaperone network that balances the expression of                            inducible HSP70 chaperones at the posttranslational level. CHIP is able                            to mediate the ubiquitylation of inducible HSP70s and induces their                            proteasomal degradation. Association of HSPBP1 or BAG2 with the                            HSP70/CHIP complex results in an inhibition of CHIP activity, leading to                            stabilization of inducible HSP70s. *Present study; (1) Jiang et al. (2001),                            (2) Qian et al.                                (2006), (3) Sasaki                                    et al. (2008).
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Figure 7: Role of HSPBP1 and BAG2 as regulators of CHIP-mediated degradation. (A) Schematic presentation of the HSP70/cochaperone network that regulates CHIP-mediated protein degradation. CHIP binds to the carboxy terminus of HSP70 and ubiquitylates the chaperone and bound client proteins in conjunction with ubiquitin-conjugating enzymes of the UBCH4/5 family. Targeting to the proteasome is assisted by the cochaperone BAG1, whereas binding of BAG3 to the chaperone/CHIP complex induces the lysosomal degradation of the client. HSPBP1 and BAG2 inhibit the ubiquitin ligase activity of CHIP in the assembled chaperone complex and thereby facilitate the folding of the client. (B) Schematic presentation of the CHIP/HSPBP1/BAG2 cochaperone network that balances the expression of inducible HSP70 chaperones at the posttranslational level. CHIP is able to mediate the ubiquitylation of inducible HSP70s and induces their proteasomal degradation. Association of HSPBP1 or BAG2 with the HSP70/CHIP complex results in an inhibition of CHIP activity, leading to stabilization of inducible HSP70s. *Present study; (1) Jiang et al. (2001), (2) Qian et al. (2006), (3) Sasaki et al. (2008).
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.

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Related in: MedlinePlus