The BAG-1 isoform BAG-1M regulates keratin-associated Hsp70 chaperoning of aPKC in intestinal cells during activation of inflammatory signaling

Anastasia Mashukova, Zhanna Kozhekbaeva, Radia Forteza, Vipin Dulam, Yolanda Figueroa, Robert Warren, Pedro J. Salas

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Atypical PKC (ι/λ and ζ hereafter referred to as aPKC) is a key player in the acquisition of epithelial polarity and participates in other signaling cascades including the control of NF-κB signaling. This kinase is post-translationally regulated through Hsp70-mediated refolding. Previous work has shown that such a chaperoning activity is specifically localized to keratin intermediate filaments. Our work was performed with the goal of identifying the molecule(s) that block Hsp70 activity on keratin filaments during inflammation. A transcriptional screen allowed us to focus on BAG-1, a multifunctional protein that assists Hsp70 in nucleotide exchange but also blocks its activity at higher concentrations. We found the BAG-1 isoform BAG-1M upregulated threefold in human Caco-2 cells following stimulation with tumor necrosis factor receptor α (TNFα) to induce a pro-inflammatory response, and up to sixfold in mouse enterocytes following treatment with dextran sodium sulfate (DSS) to induce colitis. BAG-1M, but no other isoform, was found to copurify with intermediate filaments and block Hsp70 activity in the keratin fraction but not in the soluble fraction within the range of concentrations found in epithelial cells cultured under control and inflammation conditions. Constitutive expression of BAG-1M decreased levels of phosphorylated aPKC. By contrast, knockdown of BAG-1, blocked the TNFα-induced decrease of phosphorylated aPKC. We conclude that BAG-1M mediates Hsp70 inhibition downstream of NF-κB.

Original languageEnglish (US)
Pages (from-to)3568-3577
Number of pages10
JournalJournal of Cell Science
Volume127
Issue number16
DOIs
StatePublished - 2014

Keywords

  • Epithelial polarity
  • Intermediate filaments
  • Polarized signaling

ASJC Scopus subject areas

  • Cell Biology

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