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Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation.
Espinoza, Mateo F; Nguyen, Khanh K; Sycks, Melody M; Lyu, Ziqi; Quanrud, Guy M; Montoya, Maureen R; Genereux, Joseph C.
Afiliación
  • Espinoza MF; Graduate Program in Microbiology, University of California, Riverside, California, USA.
  • Nguyen KK; Department of Chemistry, University of California, Riverside, California, USA.
  • Sycks MM; Department of Chemistry, University of California, Riverside, California, USA.
  • Lyu Z; Department of Chemistry, University of California, Riverside, California, USA.
  • Quanrud GM; Department of Chemistry, University of California, Riverside, California, USA.
  • Montoya MR; Department of Chemistry, University of California, Riverside, California, USA.
  • Genereux JC; Graduate Program in Microbiology, University of California, Riverside, California, USA; Department of Chemistry, University of California, Riverside, California, USA. Electronic address: joeygenereux@gmail.com.
J Biol Chem ; 298(12): 102597, 2022 12.
Article en En | MEDLINE | ID: mdl-36244454
Most eukaryotic secretory proteins are cotranslationally translocated through Sec61 into the endoplasmic reticulum (ER). Because these proteins have evolved to fold in the ER, their mistargeting is associated with toxicity. Genetic experiments have implicated the ER heat shock protein 70 (Hsp70) Hspa13/STCH as involved in processing of nascent secretory proteins. Herein, we evaluate the role of Hspa13 in protein import and the maintenance of cellular proteostasis in human cells, primarily using the human embryonic kidney 293T cell line. We find that Hspa13 interacts primarily with the Sec61 translocon and its associated factors. Hspa13 overexpression inhibits translocation of the secreted protein transthyretin, leading to accumulation and aggregation of immature transthyretin in the cytosol. ATPase-inactive mutants of Hspa13 further inhibit translocation and maturation of secretory proteins. While Hspa13 overexpression inhibits cell growth and ER quality control, we demonstrate that HSPA13 knockout destabilizes proteostasis and increases sensitivity to ER disruption. Thus, we propose that Hspa13 regulates import through the translocon to maintain both ER and cytosolic protein homeostasis. The raw mass spectrometry data associated with this article have been deposited in the PRIDE archive and can be accessed at PXD033498.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteostasis / Proteínas de Choque Térmico Límite: Humans Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteostasis / Proteínas de Choque Térmico Límite: Humans Idioma: En Revista: J Biol Chem Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos