title: Chaperone gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors.
abstract: HSP90 chaperones a large number of proteins, and it plays essential roles in multiple signaling pathways to maintain protein homeostasis in the cytosol. In addition, HSP90 has been implicated in mediating recognition of lipopolysaccharide (LPS). However, no pharmacologic agents have been developed to interrogate this pathway. Herein we demonstrate that a peptide-based inhibitor that was previously reported to inhibit the master Toll-like receptor-chaperone gp96, an endoplasmic reticulum paralog of HSP90, in fact blocks HSP90-LPS interaction. It inhibited the binding of LPS to the cell surface of both wild type and gp96-null cells and thereby abrogated the cellular response to LPS but not to other Toll-like receptor ligands. We also generated a series of peptide derivatives (named peptide inhibitors of endotoxin responsiveness (PIERs)) from the N-terminal helix structure of HSP90 and demonstrated their effectiveness in blocking LPS activity. PIER inhibition of LPS signaling was partially reversed by CD14 expression. Moreover, we found that a cell-permeable PIER abrogated HSP90 function and caused degradation of multiple known HSP90 client proteins in cancer cells. Thus, targeting HSP90 is a promising modality for treatment of both LPS-mediated pathology and cancer.
authors.affiliation: Departments of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.forename: Krystal
authors.initials: K
authors.lastname: Dole
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Abu Shadat M
authors.initials: AS
authors.lastname: Noman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Issacs
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D040681:Structural Homology, Protein
chemical_list: D057846:Cell-Penetrating Peptides; D018841:HSP90 Heat-Shock Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C053387:endoplasmin