Extracellular and Non-Chaperone Function of Heat Shock Protein-90α Is Required for Skin Wound Healing

JOURNAL OF INVESTIGATIVE DERMATOLOGY

卷:138

Article

Bhatia, Ayesha¹  O'Brien, Kathryn¹  Guo, Jiacong¹  Lincoln, Vadim¹  Kajiwara, Chiaki²  Chen, Mei¹  Woodley, David T.¹  Udono, Heiichiro³  Li, Wei¹ 

[1] Univ Southern Calif, Keck Med Ctr, USC Norris Comprehens Canc Ctr, Dept Dermatol, 1441 Eastlake Ave, Los Angeles, CA 90089 USA

[2] Toho Univ, Sch Med, Dept Microbiol & Infect Dis, Tokyo, Japan

[3] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Immunol, Okayama, Japan

DOI  :  10.1016/j.jid.2017.08.043

来源: Elsevier

【 摘 要 】

Despite years of effort and investment, there are few topical or systemic medications for skin wounds. Identifying natural drivers of wound healing could facilitate the development of new and effective treatments. When skin is injured, there is a massive increase of heat shock protein (Hsp) 90 alpha inside the wound bed. The precise role for these Hsp90 alpha proteins, however, was unclear. The availability of a unique mouse model that lacked the intracellular ATPase-driven chaperoning, but spared the extracellular fragment-5-supported pro-motility function of Hsp90 alpha allowed us to test specifically the role of the non-chaperone function of Hsp90 alpha in normal wound closure. We found that the chaperone-defective Hsp90 alpha-D mutant mice showed similar wound closure rate as the wild-type Hsp90 alpha mice. We generated recombinant proteins from the mouse cDNAs encoding the Hsp90 alpha-D and wild-type Hsp90 alpha. Topical application of Hsp90 alpha-D mutant protein promoted wound closure as effectively as the full-length wild-type Hsp90 alpha protein. More importantly, selective inhibition of the extracellular Hsp90 alpha-D protein function by a monoclonal antibody targeting the fragment-5 region disrupted normal wound closure in both wild-type Hsp90 alpha and Hsp90 alpha-D mice. Thus, this study provides direct support for non-chaperone, extracellular Hsp90 alpha as a potential driver for normal wound closure.

【 授权许可】

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