Dataset Information

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

ABSTRACT: 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? inside the wound bed. The precise role for these Hsp90? 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? allowed us to test specifically the role of the non-chaperone function of Hsp90? in normal wound closure. We found that the chaperone-defective Hsp90?-? mutant mice showed similar wound closure rate as the wild-type Hsp90? mice. We generated recombinant proteins from the mouse cDNAs encoding the Hsp90?-? and wild-type Hsp90?. Topical application of Hsp90?-? mutant protein promoted wound closure as effectively as the full-length wild-type Hsp90? protein. More importantly, selective inhibition of the extracellular Hsp90?-? protein function by a monoclonal antibody targeting the fragment-5 region disrupted normal wound closure in both wild-type Hsp90? and Hsp90?-? mice. Thus, this study provides direct support for non-chaperone, extracellular Hsp90? as a potential driver for normal wound closure.

SUBMITTER: Bhatia A

PROVIDER: S-EPMC6559362 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Bhatia Ayesha A O'Brien Kathryn K Guo Jiacong J Lincoln Vadim V Kajiwara Chiaki C Chen Mei M Woodley David T DT Udono Heiichiro H Li Wei W

The Journal of investigative dermatology 20170920 2

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) 90α inside the wound bed. The precise role for these Hsp90α proteins, however, was unclear. The availability of a unique mouse model that lacked the intracellular ATPase-driven chaperoning, but spared the ext ...[more]

PMID: 28942361

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Project description:BACKGROUND: A small heat shock protein AgsA was originally isolated from Salmonella enterica serovar Typhimurium. We previously demonstrated that AgsA was an effective chaperone that could reduce the amount of heat-aggregated proteins in an Escherichia coli rpoH mutant. AgsA appeared to promote survival at lethal temperatures by cooperating with other chaperones in vivo. To investigate the aggregation prevention mechanisms of AgsA, we constructed N- or C-terminal truncated mutants and compared their properties with wild type AgsA. RESULTS: AgsA showed significant overall homology to wheat sHsp16.9 allowing its three-dimensional structure to be predicted. Truncations of AgsA until the N-terminal 23rd and C-terminal 11th amino acid (AA) from both termini preserved its in vivo chaperone activity. Temperature-controlled gel filtration chromatography showed that purified AgsA could maintain large oligomeric complexes up to 50 degrees C. Destabilization of oligomeric complexes was observed for N-terminal 11- and 17-AA truncated AgsA; C-terminal 11-AA truncated AgsA could not form large oligomeric complexes. AgsA prevented the aggregation of denatured lysozyme, malate dehydrogenase (MDH) and citrate synthase (CS) but did not prevent the aggregation of insulin at 25 degrees C. N-terminal 17-AA truncated AgsA showed no chaperone activity towards MDH. C-terminal 11-AA truncated AgsA showed weak or no chaperone activity towards lysozyme, MDH and CS although it prevented the aggregation of insulin at 25 degrees C. When the same amount of AgsA and C-terminal 11-AA truncated AgsA were mixed (half of respective amount required for efficient chaperone activities), good chaperone activity for all substrates and temperatures was observed. Detectable intermolecular exchanges between AgsA oligomers at 25 degrees C were not observed using fluorescence resonance energy transfer analysis; however, significant exchanges between AgsA oligomers and C-terminal truncated AgsA were observed at 25 degrees C. CONCLUSIONS: Our data demonstrate that AgsA has several regions necessary for efficient chaperone activity: region(s) important for lysozyme chaperone activity are located outer surface of the oligomeric complex while those region(s) important for insulin are located inside the oligomeric complex and those for MDH are located within the N-terminal arm. In addition, the equilibrium between the oligomer and the dimer structures appears to be important for its efficient chaperone activity.

Dataset Information

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

Publications

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

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