{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:38:55Z","timestamp":1791833935020,"version":"4.3.4"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Vascular calcification is highly prevalent in patients with chronic kidney disease (CKD), and the underlying mechanisms remain elusive. Several studies have indicated an important role of protein ubiquitination in vascular calcification. However, the role of E3 ubiquitin ligases in vascular calcification remains poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Calcification of vascular smooth muscle cells (VSMCs) was induced by high phosphate. CKD mouse model was induced by an adenine diet, and CKD rat model was established using 5\/6 nephrectomy method. Adenovirus, siRNA (small interfering RNA), adeno-associated virus, and smooth muscle cell\u2013specific\n              <jats:italic toggle=\"yes\">TRIM16<\/jats:italic>\n              (tripartite motif 16) knockout mice were used to investigate the role of TRIM16 in vascular calcification. Immunoprecipitation\u2013mass spectrometry, and ubiquitination assay were used to dissect how TRIM16 regulates vascular calcification.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Bioinformatic analysis suggested that E3 ubiquitin ligase TRIM16 could be a key modulator of vascular calcification. TRIM16 expression was increased during vascular calcification. Overexpression of\n              <jats:italic toggle=\"yes\">TRIM16<\/jats:italic>\n              exacerbated VSMC calcification and aortic calcification of CKD rats. By contrast, the knockdown of\n              <jats:italic toggle=\"yes\">TRIM16<\/jats:italic>\n              alleviated VSMC calcification and aortic calcification in CKD rats. Moreover, the deletion of\n              <jats:italic toggle=\"yes\">TRIM16<\/jats:italic>\n              inhibited VSMC calcification and aortic calcification in VitD3 (vitamin D3)-overloaded mice and CKD mice. Mechanistically, immunoprecipitation\u2013mass spectrometry revealed that DAB2 (disabled homolog 2) was the potential downstream target of TRIM16. Coimmunoprecipitation showed that the SPRY (SPla and the RYanodine receptor) domain of TRIM16 interacted with the proline-rich domain of DAB2. Moreover, ubiquitination assay revealed that the SPRY domain of TRIM16 is required for TRIM16-mediated K63-linked ubiquitination of DAB2 at K656 residue. Of note, the knockdown of\n              <jats:italic toggle=\"yes\">DAB2<\/jats:italic>\n              inhibited TRIM16-induced VSMC calcification. Furthermore, knockdown of\n              <jats:italic toggle=\"yes\">DAB2<\/jats:italic>\n              antagonized endocytosis of integrin \u03b21 and subsequent activation of FAK (focal adhesion kinase)-STAT3 (signal transduction and transcriptional activation factor 3) signaling induced by overexpression of\n              <jats:italic toggle=\"yes\">TRIM16<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Our study for the first time demonstrates that E3 ubiquitin ligase TRIM16 catalyzes K63-ubiquitination of the endocytic adaptor DAB2, leading to endocytosis of integrin \u03b21 and activation of FAK-STAT3 signaling, and subsequently exacerbates vascular calcification, suggesting that TRIM16-DAB2 axis is a promising therapeutic target for vascular calcification.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.125.326520","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T05:00:25Z","timestamp":1751000425000},"page":"551-568","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["TRIM16 Mediates K63-Linked Ubiquitination of DAB2 to Facilitate Vascular Calcification"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7086-8996","authenticated-orcid":true,"given":"Zirong","family":"Lan","sequence":"first","affiliation":[{"name":"Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9318-2357","authenticated-orcid":true,"given":"Qingchun","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, China (Q.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8857-1900","authenticated-orcid":true,"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, China (L. 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Zhujiang Hospital, Southern Medical University, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9455-7597","authenticated-orcid":true,"given":"Yuanzhi","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation (Z.L., F.L., A.C., Y.Y., L.F., Z.Z., X.Z., J.Y.)."},{"name":"Guangdong Provincial 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