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Missense mutations in keratin 5 (K5; also known as KRT5) or keratin 14 (K14; also known as KRT14), highly expressed in the basal epidermis, cause the severe skin blistering disease epidermolysis bullosa simplex (EBS). EBS-associated mutations disrupt keratin networks and change keratinocyte mechanics; however, molecular mechanisms by which mutations shape EBS pathology remain incompletely understood. Here, we demonstrate that, in contrast to keratin-deficient keratinocytes, cells expressing K14R125C, a mutation that causes severe EBS, generate lower traction forces, accompanied by immature focal adhesions with an altered cellular distribution. Furthermore, mutant keratinocytes display reduced directionality during collective migration. Notably, RhoA activity is downregulated in human EBS keratinocytes, and Rho activation rescues stiffness-dependent cell\u2013extracellular matrix (ECM) adhesion formation of EBS keratinocytes. Collectively, our results strongly suggest that intact keratin IF networks regulate mechanotransduction through a Rho signaling pathway upstream of cell\u2013ECM adhesion formation and organized cell migration. Our findings provide insights into the underlying pathophysiology of EBS.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/jcs.243956","type":"journal-article","created":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T20:27:28Z","timestamp":1593721648000},"source":"Crossref","is-referenced-by-count":27,"title":["Disease-associated keratin mutations reduce traction forces and compromise adhesion and collective migration"],"prefix":"10.1242","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5620-637X","authenticated-orcid":false,"given":"Sachiko","family":"Fujiwara","sequence":"first","affiliation":[{"name":"Institute of Biology 1 , Faculty of Life Sciences , , Leipzig 04103 , Germany"},{"name":"University of Leipzig 1 , Faculty of Life Sciences , , Leipzig 04103 , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Deguchi","sequence":"additional","affiliation":[{"name":"Graduate School of Engineering Science, Osaka University 2 Division of Bioengineering , , Toyonaka 560-8531 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-2409","authenticated-orcid":false,"given":"Thomas M.","family":"Magin","sequence":"additional","affiliation":[{"name":"Institute of Biology 1 , Faculty of Life Sciences , , Leipzig 04103 , Germany"},{"name":"University of Leipzig 1 , Faculty of Life Sciences , , Leipzig 04103 , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"2024061318540720700_JCS243956C1","doi-asserted-by":"publisher","first-page":"3053","DOI":"10.1016\/j.bbamcr.2015.05.009","article-title":"Physical properties of cytoplasmic intermediate filaments","volume":"1853","author":"Block","year":"2015","journal-title":"Biochim. 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