{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:54:31Z","timestamp":1792198471920,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T00:00:00Z","timestamp":1642896000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16H05175"],"award-info":[{"award-number":["16H05175"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:p>Hepatocyte growth factor activator inhibitor\u20101 (HAI\u20101, also known as SPINT1) is an inhibitor of matriptase, a type\u20102 transmembrane protease widely expressed in epithelial cells. HAI\u20101 also functions as a chaperone to maintain the processing and localization of matriptase required for epithelial integrity. However, mechanisms underpinning the chaperone function remain to be elucidated. Here, we show that the first Kunitz domain (KD1) and the adjacent polycystic kidney disease (PKD) domain\u2010like internal domain of HAI\u20101 are essential for the chaperone function. In HEK293T cells, which do not express endogenous HAI\u20101 or matriptase, forced matriptase overexpression was unsuccessful unless sufficient HAI\u20101 was co\u2010expressed. Among mutant HAI\u20101 constructs, HAI\u20101 with inactivation mutation in KD1 (HAI\u20101mKD1) or HAI\u20101 lacking the PKD domain (HAI\u20101dPKD) was unable to support matriptase expression, and neither mutant formed a complex with activated matriptase. Matriptase did not localize to the cell surface when co\u2010expressed with HAI\u20101dPKD. Moreover, HAI\u20101dPKD accumulated in the cytoplasm of HEK293T and HaCaT cells rather than localizing to the cell surface, presumably due to misfolding as judged by altered antibody recognition. On the other hand, activationlocked and activity\u2010incompetent matriptase were stable and readily overexpressed and localized to the cell surface without HAI\u20101. Therefore, the observed matriptase instability was caused by its own catalytic activity in the absence of inhibitory HAI\u20101. The matriptase chaperone function of HAI\u20101 is thus mediated primarily by the inhibition of undesired intracellular matriptase activity, and the PKD domain is essential for the proper folding and trafficking of inhibitory HAI\u20101 and its chaperone function.<\/jats:p>","DOI":"10.1111\/febs.16348","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T10:17:18Z","timestamp":1641982638000},"page":"3422-3439","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Role of the polycystic kidney disease domain in matriptase chaperone activity and localization of hepatocyte growth factor activator inhibitor\u20101"],"prefix":"10.1111","volume":"289","author":[{"given":"Fumiki","family":"Yamashita","sequence":"first","affiliation":[{"name":"Section of Oncopathology and Regenerative Biology Department of Pathology, Faculty of Medicine, University of Miyazaki  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