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The study identifies cyclophilin J (CYPJ) as a negative regulator of LUBAC. CYPJ binds the NZF domain of HOIL-1-interacting protein and the ubiquitin-like domain of SHARPIN to disrupt their interaction, thereby restraining linear ubiquitin chain synthesis and NF-kB activation. Cypj-deficient mice show increased DSS-colitis and DSS/azoxymethane colon cancer susceptibility. CYPJ is induced by hypoxia, and elevated CYPJ with HIF-1a correlates with improved survival, implicating CYPJ as a robust attenuator of inflammation-driven tumorigenesis.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/cyclophilin-j-limits-linear-ubiquitin-signaling-and-controls-colorectal-cancer-progression/331275/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/cyclophilin-j-limits-linear-ubiquitin-signaling-and-controls-colorectal-cancer-progression/331275.png","ImageObject",300,407,{"name":92,"@type":93},"Theodore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does cyclophilin J (CYPJ) play in linear ubiquitin signaling?","Question",{"text":112,"@type":113},"CYPJ functions as a negative regulator of the linear ubiquitin chain assembly complex (LUBAC), restraining linear ubiquitin chain synthesis and downstream NF-kB activation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does CYPJ interfere with LUBAC activity at the molecular level?",{"text":117,"@type":113},"CYPJ uses its N terminus to bind domains on HOIL-1-interacting protein and SHARPIN, disrupting their interaction and reducing LUBAC-driven linear ubiquitination.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the impact of CYPJ loss or hypoxia-induced CYPJ in colorectal cancer models and patients?",{"text":121,"@type":113},"Cypj-deficient mice are more susceptible to DSS-induced colitis and DSS plus azoxymethane-induced colon cancer. In patients, high CYPJ expression together with hypoxia-inducible factor-1a associates with longer overall survival and progression-free survival.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},331275,1790710353,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36,"preview_page_count":4},7971461740886,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","RESEARCH ARTICLE  \nCyclophilin J limits linear ubiquitin signaling and controls colorectal cancer progression  \nReceived for publication, January 10, 2024, and in revised form, July 4, 2024 Published, Papers in Press, July 27, 2024, [https://doi.org/10.1016/j.jbc.2024.107610](https://doi.org/10.1016/j.jbc.2024.107610)  \nChunjie Sheng*, Chen Yao, Jing Wang, Yizhi Mao, Lingyi Fu, and Shuai Chen*  \nFrom the State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yatsen University Cancer Center, Guangzhou, PR China  \nReviewed by members of the JBC Editorial Board. Edited by Paul Shapiro  \nExorbitant sustained inflammation is closely linked to inflammation-associated disorders, including cancer. The initiation of gastrointestinal cancers such as colorectal cancer is frequently accelerated by uncontrollable chronic inflammation which is triggered by excessive activation of nuclear factor kappa-B (NF-kB) signaling. Linear ubiquitin chains play an important role in activating canonical NF-kB pathway. The only known E3 complex, linear ubiquitin chain assembly complex is responsible for the synthesis of linear ubiquitin chains, thus leading to the activation of NF-kB axis and promoting the development of inflammation and inflammationassociated cancers. We report here cyclophilin J (CYPJ) which is a negative regulator of the linear ubiquitin chain assembly complex. The N terminus of CYPJ binds to the second Npl4 zinc finger (NZF) domain of HOIL-1-interacting protein and the ubiquitin-like domain of Shank-associated RH domain-interacting protein to disrupt the interaction between HOIL-1-interacting protein and Shank-associated RH domaininteracting protein and thus restrains linear ubiquitin chain synthesis and NF-kB activation. Cypj-deficient mice are highly susceptible to dextran sulfate sodium-induced colitis and dextran sulfate sodium plus azoxymethane-induced colon cancer. Moreover, CYPJ expression is induced by hypoxia. Patients with high expression of both CYPJ and hypoxiainducible factor-1a have longer overall survival and progression-free survival. These results implicate CYPJ as an unexpected robust attenuator of inflammation-driven tumorigenesis that exerts its effects by controlling linear ubiquitin chain synthesis in NF-kB signal pathway.  \nThe linear ubiquitin chain assembly complex (LUBAC) is composed of three members: the catalytic subunit HOIL-1-interacting protein (HOIP) and two regulatory subunits, longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) and Shank-associated RH domain-interacting protein (SHARPIN) (1, 2). As the only known 600-kD multimeric E3 ligase, LUBAC is responsible for peptide bond formation between the C-terminal glycine (G76) of one ubiquitin and the a-NH2 group of methionine 1 (M1) of  \n* For correspondence: Chunjie Sheng, [shengchj@sysucc.org.cn](shengchj@sysucc.org.cn); Shuai Chen, [chenshuai@sysucc.org.cn](chenshuai@sysucc.org.cn).  \nanother ubiquitin. In response to pathogen infections, the linear ubiquitin chain (also known as the M1-linked linear ubiquitin chains; we refer to it as M1-Ub for short) is generated by the LUBAC and plays a vital role in triggering inflammatory pathways such as nuclear factor kappa-B (NF-kB) and activated protein-1 (AP-1) (3, 4). The E3 activity of HOIPis indispensable for the activation of the canonical NF-kB pathway through linear ubiquitination of NEMO (IKKg), and thus, HOIP-deficient cells are sensitive to tumor necrosis factor (TNF) and lymphotoxin-a-mediated apoptosis and necroptosis. Genetic ablation of Hoip or Hoil-1l results in embryonic lethality mainly due to TNF-induced cell death of endothelial cells (5), while mice with Sharpin deficiency develop chronic proliferative dermatitis (referred to as cpdm mice) (6). Generally, the M1-Ub signal contributes to cell survival while some deubiquitinase such as OTULIN or CYLD hydrolyzes linear ubiquitin chains to inhibit host inflammati","cbCaih04R6GpqILm","https://ap.wps.com/l/cbCaih04R6GpqILm","pdf",5166290,16,"English","# Introduction\n# Linear ubiquitin chain assembly and NF-kB signaling\n# CYPJ as a negative regulator of LUBAC\n# In vivo and clinical implications","[{\"question\":\"What role does cyclophilin J (CYPJ) play in linear ubiquitin signaling?\",\"answer\":\"CYPJ functions as a negative regulator of the linear ubiquitin chain assembly complex (LUBAC), restraining linear ubiquitin chain synthesis and downstream NF-kB activation.\"},{\"question\":\"How does CYPJ interfere with LUBAC activity at the molecular level?\",\"answer\":\"CYPJ uses its N terminus to bind domains on HOIL-1-interacting protein and SHARPIN, disrupting their interaction and reducing LUBAC-driven linear ubiquitination.\"},{\"question\":\"What is the impact of CYPJ loss or hypoxia-induced CYPJ in colorectal cancer models and patients?\",\"answer\":\"Cypj-deficient mice are more susceptible to DSS-induced colitis and DSS plus azoxymethane-induced colon cancer. In patients, high CYPJ expression together with hypoxia-inducible factor-1a associates with longer overall survival and progression-free survival.\"}]","Cyclophilin J limits linear ubiquitin signaling and controls colorectal cancer progression | PDF",1789992514]