{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T13:13:54Z","timestamp":1783602834700,"version":"3.55.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["NSTC 113-2320-B-039-024-MY3"],"award-info":[{"award-number":["NSTC 113-2320-B-039-024-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["CMU113-MF-13"],"award-info":[{"award-number":["CMU113-MF-13"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Dengue virus (DENV) and Zika virus (ZIKV) are medically important orthoflaviviruses that utilize the multifunctional NS3 protease, in complex with its cofactor NS2B, for viral replication and host modulation. Here, we summarize current knowledge of host proteins targeted by NS3 proteases and discuss recent advances in proteomic and computational approaches for identifying these substrates. We further discuss evidence showing that NS2B3-mediated cleavage alters innate immune signaling, autophagy, protein translation, and cytoskeletal dynamics. In addition, we compare the host substrate specificities of DENV and ZIKV proteases, emphasizing both shared mechanisms and virus-specific differences that may contribute to their distinct disease manifestations. A deeper understanding of NS3-mediated host protein cleavage will provide critical insights into orthoflavivirus biology and further establish NS3 as a promising target for antiviral intervention.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1899950","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T12:18:56Z","timestamp":1783599536000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Host protein cleavage by Dengue and Zika virus NS3 proteases: from substrate identification to potential biological consequences"],"prefix":"10.3389","volume":"16","author":[{"given":"Umar","family":"Saidu","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University","place":["Taichung, Taiwan"]},{"name":"Department of Biochemistry, Ahmadu Bello University","place":["Zaria, Nigeria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bbumba","family":"Patrick","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chi","family":"Su","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Sciences, China Medical University","place":["Taichung, Taiwan"]},{"name":"International Master\u2019s Program of Biomedical Sciences, China Medical University","place":["Taichung, Taiwan"]},{"name":"Department of Medical Research, China Medical University Hospital","place":["Taichung, Taiwan"]},{"name":"Drug Development Center, China Medical University","place":["Taichung, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002934","article-title":"DENV inhibits type I IFN production in infected cells by cleaving human STING","volume":"8","author":"Aguirre","year":"2012","journal-title":"PloS Pathog."},{"key":"B2","doi-asserted-by":"publisher","first-page":"8968","DOI":"10.3390\/ijms26188968","article-title":"The impacts of dengue virus infection on mitochondrial functions and dynamics","volume":"26","author":"Ahmed","year":"2025","journal-title":"Int. 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