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PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

التفاصيل البيبلوغرافية
العنوان: PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.
المؤلفون: Yang CL; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Wang FX; Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China., Luo JH; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Rong SJ; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Lu WY; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Chen QJ; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Xiao J; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Wang T; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Song DN; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Liu J; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Mo Q; Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China., Li S; Department of Clinical Laboratory, Institute of Translational Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, China., Chen Y; Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China., Wang YN; Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Liu YJ; The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiao-tong University, the Third People's Hospital of Chengdu, Chengdu 610031, China., Yan T; The Center for Obesity and Metabolic Health, Affiliated Hospital of Southwest Jiao-tong University, the Third People's Hospital of Chengdu, Chengdu 610031, China., Gu WK; Research Service, Memphis VA Medical Center, Memphis, TN 38105, USA., Zhang S; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Xiong F; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Yu QL; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Zhang ZY; Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China., Yang P; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China., Liu SW; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan 030032, China., Eizirik D; ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium., Dong LL; Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: tjhdongll@163.com., Sun F; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: phil_sunfei@163.com., Wang CY; Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan 030032, China. Electronic address: wangcy@tjh.tjmu.edu.cn.
المصدر: Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Aug 07; Vol. 32 (8), pp. 2778-2797. Date of Electronic Publication: 2024 May 31.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE
أسماء مطبوعة: Publication: 2017- : Cambridge, MA : Cell Press
Original Publication: San Diego, CA : Academic Press, 2000-
مواضيع طبية MeSH: Protein Disulfide-Isomerases*/metabolism , Protein Disulfide-Isomerases*/genetics , Arthritis, Rheumatoid*/metabolism , STAT1 Transcription Factor*/metabolism, Humans ; Mice ; Animals ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Active Transport, Cell Nucleus ; Carrier Proteins/metabolism ; Signal Transduction ; Thyroid Hormone-Binding Proteins ; NFATC Transcription Factors/metabolism ; Lymphocyte Activation ; Thyroid Hormones/metabolism ; Gene Expression Regulation ; Th17 Cells/metabolism ; Th17 Cells/immunology ; Th1 Cells/immunology ; Th1 Cells/metabolism ; Disease Models, Animal ; Pyruvate Kinase
مستخلص: Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.
Competing Interests: Declaration of interests The authors declare that they have no conflict of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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فهرسة مساهمة: Keywords: PDIA3; effector T cell program; non-canonical function; nuclear transport; rheumatoid arthritis
المشرفين على المادة: EC 5.3.4.1 (Protein Disulfide-Isomerases)
0 (STAT1 Transcription Factor)
EC 5.3.4.1. (PDIA3 protein, human)
0 (Membrane Proteins)
0 (Carrier Proteins)
EC 2.7.1.40 (Pkm protein, mouse)
0 (Thyroid Hormone-Binding Proteins)
0 (NFATC Transcription Factors)
0 (Thyroid Hormones)
EC 5.3.4.1 (Pdia3 protein, mouse)
EC 2.7.1.40 (Pyruvate Kinase)
تواريخ الأحداث: Date Created: 20240601 Date Completed: 20240808 Latest Revision: 20240921
رمز التحديث: 20240921
مُعرف محوري في PubMed: PMC11405166
DOI: 10.1016/j.ymthe.2024.05.038
PMID: 38822524
قاعدة البيانات: MEDLINE
الوصف
تدمد:1525-0024
DOI:10.1016/j.ymthe.2024.05.038