N-Terminomics/TAILS Profiling of Proteases and Their Substrates in Ulcerative Colitis.,ACS Chemical Biology

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N-Terminomics/TAILS Profiling of Proteases and Their Substrates in Ulcerative Colitis.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-08-21 , DOI: 10.1021/acschembio.9b00608
Marilyn H Gordon ₁ , Anthonia Anowai _{2,

3} , Daniel Young _{1,

3} , Nabangshu Das _{1,

3} , Rhiannon I Campden _{2,

4} , Henna Sekhon _{1,

3} , Zoe Myers _{1,

3} , Barbara Mainoli _{1,

3} , Sameeksha Chopra _{1,

3} , Peter S Thuy-Boun ₅ , Jayachandran Kizhakkedathu ₆ , Gurmeet Bindra ₇ , Humberto B Jijon ₇ , Steven Heitman ₇ , Robin Yates ₄ , Dennis W Wolan ₅ , Laura E Edgington-Mitchell _{8,

9,

10} , Wallace K MacNaughton ₁ , Antoine Dufour _{1,

2,

3}

Affiliation

Department of Physiology and Pharmacology , University of Calgary , Calgary , Alberta , Canada T2N 4N1.
Department of Biochemistry and Molecular Biology , University of Calgary , Calgary , Alberta , Canada T2N 4N1.
McCaig Institute for Bone and Joint Health , University of Calgary , Calgary , Alberta , Canada T2N 4N1.
Department of Comparative Biology and Experimental Medicine , University of Calgary , Calgary , Alberta , Canada T2N 4N1.
Departments of Molecular Medicine and Integrative Structural and Computational Biology , The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
Department of Pathology and Laboratory Medicine and Department of Chemistry , University of British Columbia , Vancouver , British Columbia V6T 1Z2 , Canada.
Department of Medicine, Division of Gastroenterology , University of Calgary , Calgary , Alberta , Canada T2N 4N1.
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute , The University of Melbourne , Victoria , Parkville , Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences , Monash University , Parkville , Victoria , Australia.
Department of Oral and Maxillofacial Surgery , New York University College of Dentistry, Bluestone Center for Clinical Research , New York , New York , United States.

Dysregulated protease activity is often implicated in the initiation of inflammation and immune cell recruitment in gastrointestinal inflammatory diseases. Using N-terminomics/TAILS (terminal amine isotopic labeling of substrates), we compared proteases, along with their substrates and inhibitors, between colonic mucosal biopsies of healthy patients and those with ulcerative colitis (UC). Among the 1642 N-termini enriched using TAILS, increased endogenous processing of proteins was identified in UC compared to healthy patients. Changes in the reactome pathways for proteins associated with metabolism, adherens junction proteins (E-cadherin, liver-intestinal cadherin, catenin alpha-1, and catenin delta-1), and neutrophil degranulation were identified between the two groups. Increased neutrophil infiltration and distinct proteases observed in ulcerative colitis may result in extensive break down, altered processing, or increased remodeling of adherens junctions and other cellular functions. Analysis of the preferred proteolytic cleavage sites indicated that the majority of proteolytic activity and processing comes from host proteases, but that key microbial proteases may also play a role in maintaining homeostasis. Thus, the identification of distinct proteases and processing of their substrates improves the understanding of dysregulated proteolysis in normal intestinal physiology and ulcerative colitis.

中文翻译：

溃疡性结肠炎中蛋白酶及其底物的N-术语/ TAILS分析。

蛋白酶活性失调通常与胃肠炎性疾病中炎症的引发和免疫细胞募集有关。使用N-terminomics / TAILS（底物的末端胺同位素标记），我们比较了健康患者和溃疡性结肠炎（UC）患者的结肠黏膜活检组织中的蛋白酶及其底物和抑制剂。在使用TAILS富集的1642个N末端中，与健康患者相比，在UC中发现了蛋白质的内源性加工增加。在两组之间确定了与代谢相关的蛋白质，粘附连接蛋白（E-钙黏着蛋白，肝肠钙黏着蛋白，连环蛋白α-1和连环蛋白δ-1）和中性粒细胞脱粒的反应组途径的变化。在溃疡性结肠炎中观察到嗜中性粒细胞浸润增加和独特的蛋白酶可能导致广泛的破坏，改变的加工过程或粘附连接和其他细胞功能的重塑。对优选的蛋白水解切割位点的分析表明，大多数蛋白水解活性和加工过程均来自宿主蛋白酶，但关键的微生物蛋白酶也可能在维持体内平衡中发挥作用。因此，不同蛋白酶的鉴定及其底物的加工提高了对正常肠道生理和溃疡性结肠炎中蛋白水解失调的理解。对优选的蛋白水解切割位点的分析表明，大多数蛋白水解活性和加工过程均来自宿主蛋白酶，但关键的微生物蛋白酶也可能在维持体内平衡中发挥作用。因此，不同蛋白酶的鉴定及其底物的加工提高了对正常肠道生理和溃疡性结肠炎中蛋白水解失调的理解。对优选的蛋白水解切割位点的分析表明，大多数蛋白水解活性和加工过程均来自宿主蛋白酶，但关键的微生物蛋白酶也可能在维持体内平衡中发挥作用。因此，不同蛋白酶的鉴定及其底物的加工提高了对正常肠道生理和溃疡性结肠炎中蛋白水解失调的理解。

更新日期：2019-08-21

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