title: HSP70-binding protein HSPBP1 regulates chaperone expression at a posttranslational level and is essential for spermatogenesis.
abstract: Molecular chaperones play key roles during growth, development, and stress survival. The ability to induce chaperone expression enables cells to cope with the accumulation of nonnative proteins under stress and complete developmental processes with an increased requirement for chaperone assistance. Here we generate and analyze transgenic mice that lack the cochaperone HSPBP1, a nucleotide-exchange factor of HSP70 proteins and inhibitor of chaperone-assisted protein degradation. Male HSPBP1(-/-) mice are sterile because of impaired meiosis and massive apoptosis of spermatocytes. 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 demonstrate that HSPBP1 affects chaperone expression at a posttranslational level by inhibiting the ubiquitylation and proteasomal degradation of inducible HSP70 proteins. 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.
authors.affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rogon
authors.affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Ulbricht
authors.affiliation: Institut für Physiologie I, Life and Brain Centre, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53105 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hesse
authors.affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Alberti
authors.affiliation: Abteilung für Zellbiochemie, Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53115 Bonn, Germany.
authors.forename: Preethi
authors.initials: P
authors.lastname: Vijayaraj
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Diana
authors.initials: D
authors.lastname: Best
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Adams
authors.affiliation: Abteilung für Zellbiochemie, Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53115 Bonn, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Magin
authors.affiliation: Institut für Physiologie I, Life and Brain Centre, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53105 Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Institut für Zellbiologie and Bonner Forum Biomedizin, Rheinische Friedrich-Wilhelms-Universität Bonn, D-53121 Bonn, Germany hoehfeld@uni-bonn.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Höhfeld
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D015870:Gene Expression; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D013091:Spermatogenesis; D013737:Testis / Q000378:metabolism / Q000473:pathology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018840:HSP70 Heat-Shock Proteins; C000596378:HSP70-binding protein HSPBP1, mouse; C490434:Hspa2 protein, mouse