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Some of the mutations cause defects in the functionally required Kunitz domain 1 and\/or subcellular targeting signals. Almost all SCSD patients, however, harbor SPINT2 missense mutations that affect the functionally less important Kunitz domain 2. How theses single amino acid substitutions inactivate HAI-2 was, here, investigated by the doxycycline-inducible expression of three of these mutants in HAI-2-knockout Caco-2 human colorectal adenocarcinoma cells. Examining protein expressed from these HAI-2 mutants reveals that roughly 50% of the protein is synthesized as disulfide-linked oligomers that lose protease inhibitory activity due to the distortion of the Kunitz domains by disarrayed disulfide bonding. Although the remaining protein is synthesized as monomers, its glycosylation status suggests that the HAI-2 monomer remains in the immature, lightly glycosylated form, and is not converted to the heavily glycosylated mature form. Heavily glycosylated HAI-2 possesses full anti-protease activity and appropriate subcellular targeting signals, including the one embedded in the complex-type N-glycan. As predicted, these HAI-2 mutants cannot suppress the excessive prostasin proteolysis caused by HAI-2 deletion. The oligomerization and glycosylation defects have also been observed in a colorectal adenocarcinoma line that harbors one of these SPINT2 missense mutations. Our study reveals that the abnormal protein folding and N-glycosylation can cause widespread HAI-2 inactivation in SCSD patents.<\/jats:p>","DOI":"10.1093\/hmg\/ddae005","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T17:27:33Z","timestamp":1706203653000},"page":"752-767","source":"Crossref","is-referenced-by-count":6,"title":["<i>SPINT2<\/i> mutations in the Kunitz domain 2 found in SCSD patients inactivate HAI-2 as prostasin inhibitor via abnormal protein folding and N-glycosylation"],"prefix":"10.1093","volume":"33","author":[{"given":"Nanxi","family":"Huang","sequence":"first","affiliation":[{"name":"Lombardi Comprehensive Cancer Center , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"},{"name":"Georgetown University , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaochu","family":"Wang","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"},{"name":"Georgetown University , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B","family":"Bernard","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"},{"name":"Georgetown University , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao-Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, National Defense Medical Center , No. 161, sec. 6, Minquan E. Road, Neihu Dist. Taipei City 11490, Taiwan , ROC"},{"name":"Division of Colorectal Surgery , Department of Surgery, , No. 325, Sec. 2, Chenggon Road, Neihu Dist. Taipei City 114202, Taiwan , ROC"},{"name":"Tri-Service General Hospital , Department of Surgery, , No. 325, Sec. 2, Chenggon Road, Neihu Dist. Taipei City 114202, Taiwan , ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je-Ming","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Medicine, National Defense Medical Center , No. 161, sec. 6, Minquan E. Road, Neihu Dist. Taipei City 11490, Taiwan , ROC"},{"name":"Division of Colorectal Surgery , Department of Surgery, , No. 325, Sec. 2, Chenggon Road, Neihu Dist. Taipei City 114202, Taiwan , ROC"},{"name":"Tri-Service General Hospital , Department of Surgery, , No. 325, Sec. 2, Chenggon Road, Neihu Dist. Taipei City 114202, Taiwan , ROC"},{"name":"Graduate Institute of Medical Sciences, National Defense Medical Center , No. 161, sec. 6, Minquan E. Neihu Dist. Taipei City 11490, Taiwan , ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jehng-Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, National Defense Medical Center , No. 161, sec. 6, Minquan E. Road, Taipei City, 11490, Taiwan , ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khee-Siang","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, Chi Mei Medical Center , No. 901, Zhonghua Road, Yongkang Dist., Tainan City, 71004, Taiwan , ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Johnson","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"},{"name":"Georgetown University , Department of Oncology, , 3970 Reservoir Road NW W422 New Research Building, Washington DC 20057 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6391-2571","authenticated-orcid":false,"given":"Chen-Yong","family":"Lin","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive 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