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TG2 is upregulated upon cellular stress or injury, and extracellular TG2 is implicated in several human diseases, including celiac disease. However, incomplete knowledge about extracellular TG2 biology limits our understanding of how TG2 is involved in disease. Here, we demonstrate that binding of TG2 to the ECM of small intestinal tissue sections is the sum of binding to fibronectin (FN) via its N\u2010terminal domain and binding to an abundant, novel extracellular matrix (ECM) interaction partner via its second C\u2010terminal beta\u2010barrel domain. The latter interaction dominates and gives rise to the characteristic reticular staining pattern of extracellular TG2. Of relevance for celiac disease, we show that self\u2010multimerized TG2 does not efficiently deposit in the intestinal ECM, and TG2 complexes may thus become free\u2010floating antigens in tissues in contrast to monomeric TG2 that would readily become sequestered by the ECM. Upon injection of monoclonal antibody targeting the FN\u2010binding site, we observe antibody deposition on extracellular TG2 in cryosections, suggesting that the FN\u2010binding site of TG2 is exposed <jats:italic>in vivo<\/jats:italic>. This would explain how and why celiac autoantibodies recognizing the FN\u2010binding site of TG2 can bind TG2 <jats:italic>in vitro<\/jats:italic>,<jats:italic> in situ<\/jats:italic> as well as <jats:italic>in vivo<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/febs.13907","type":"journal-article","created":{"date-parts":[[2016,9,29]],"date-time":"2016-09-29T17:26:50Z","timestamp":1475170010000},"page":"3994-4010","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Transglutaminase 2 strongly binds to an extracellular matrix component other than fibronectin via its second C\u2010terminal beta\u2010barrel domain"],"prefix":"10.1111","volume":"283","author":[{"given":"Jorunn","family":"Stamnaes","sequence":"first","affiliation":[{"name":"Centre for Immune Regulation and Department of Immunology University of Oslo and Oslo University Hospital 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