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Survival and maintenance of regulatory T cells require the kinase TAK1

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Cellular & Molecular Immunology 2015年第5期12卷 572-579页

作者： Jae-Hoon Chang Hongbo Hu Shao-Cong Sun Department of Immunology The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA Center for Inflammation and Cancer The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA The University of Texas Graduate School of Biomedical Sciences at Houston Houston TX 77030 USA College of Pharmacy Yeungnam University Gyeongsan 712- 749 Republic of Korea

Regulatory T （Treg） cells play a central role in regulating peripheral immune tolerance and preventing autoimmunity. Despite the extensive studies on the development of Treg cells, the molecular mechanisms that maintain the population of committed Treg cells remain poorly understood. We show here that Treg-conditional ablation of the kinase TAK1 reduced the number of Treg cells in the peripheral lymphoid organs, causing abnormal activation of conventional T cells and autoimmune symptoms. Using an inducible gene knockout approach, we further demonstrate that TAK1 is crucial for the survival of Treg cells. Expression of a constitutively active IKB kinase partially restored the level of Treg cells in the TAKITreg-KO mice. These results suggest a crucial role for TAK1 for maintaining the survival of committed Treg cells under physiololzical conditions.

关键词： regulatory T cells autoimmunity TAK1 IKK Foxp3

Targeting ubiquitin signaling for cancer immunotherapy

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Signal Transduction and Targeted Therapy 2021年第2期6卷 372-386页

作者： Xiaofei Zhou Shao-Cong Sun Department of Immunology The Unvrsity of Texas MD Anderson Cancer Center7455 Fannin SteetBox 902HoustonTX 77030USA The University of Texas Graduate School of Biomedical Sciences HoustonTX 77030USA

Cancer immunotherapy has become an attractive approach of cancer treatment with tremendous success in treating various advanced *** development and clinical application of immune checkpoint inhibitors represent one of the most extraordinary accomplishments in cancer *** addition,considerable progress is being made in understanding the mechanism of antitumor immunity and characterizing novel targets for developing additional therapeutic *** active area of investigation is protein ubiquitination,a post-translational mechanism of protein modifcation that regulates the function of diverse immune cells in antitumor *** studies suggest that E3 ubiquitin ligases and deubiquitinases form a family of potential targets to be exploited for enhancing antitumor immunity in cancer immunotherapy.

关键词： ubiquitin immunotherapy immunity

TBK1 as a regulator of autoimmunity and antitumor immunity

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Cellular & Molecular Immunology 2018年第8期15卷 743-745页

作者： Jian-Hong Shi Xiaoping Xie Shao-Cong Sun Central Laboratory Affiliated Hospital of Hebei University212 Yuhua East RoadBaoding 07100China Department of Immunology The University of Texas MD Anderson Cancer Center7455 Fannin StreetBox 902HoustonTX 77030USA

TANK-binding kinase 1(TBK1)and its homolog IκB kinase(IKK)epsilon(IKKε,also known as IKKi)are serine/threonine kinases that are well known for their functions to mediate type I interferon(IFN-I)induction in antiviral innate immune responses.1 Various microbial components,or pathogen associated molecular patterns(PAMPs),activate TBK1 and IKKεvia stimulating pattern-recognition receptors(PRRs)in innate immune *** activation,TBK1 or IKKε(hereafter called TBK1/IKKε)phosphorylates the transcription factors IRF3 and IRF7 to trigger their dimerization and nuclear translocation,leading to induction of IFN-I gene expression.1,2 In this innate immune signaling pathway,TBK1 and IKKεdisplay functional redundancies,although TBK1 seems to be more crucial than IKKε.3,4 It is increasingly clear that the function of TBK1 and IKKεis beyond the regulation of antiviral innate immunity.

关键词： expression. immunity hereafter

Establishment and function of tissue-residenl nnate lymphoid cells in the skin

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Protein & Cell 2017年第7期8卷 489-500页

作者： Jie Yang Luming Zhao Ming Xu Na Xiong Centre for Molecular Immunology and Infectious Diseases and Department of Veterinary and Biomedical Sciences The Pennsylvania State University University Park PA 16802 USA Department of Immunology The University of Texas MD Anderson Cancer Center 7455 Fannin Street Houston TX 77054 USA

Innate lymphoid cells （ILCs） are a newly classified family of immune cells of the lymphoid lineage. While they could be found in both lymphoid organs and non-lym-phoid tissues, ILCs are preferentially enriched in barrier tissues such as the skin, intestine, and lung where they could play important roles in maintenance of tissue integrity and function and protection against assaults of foreign agents. On the other hand, dysregulated activation of ILCs could contribute to tissue inflammatory diseases. In spite of recent progress towards understanding roles of ILCs in the health and disease, mech-anisms regulating specific establishment, activation, and function of ILCs in barrier tissues are still poorly understood. We herein review the up-to-date understanding of tissue-specific relevance of ILCs. Particularly we will focus on resident ILCs of the skin, the outmost barrier tissue critical in protection against various foreign hazardous agents and maintenance of thermal and water balance. In addition, we will discuss remaining outstanding questions yet to be addressed.

关键词： innate lymphoid cells skin migration,chemokine receptor homeostasis inflammation

Deubiquitinases as pivotal regulators of T cell functions

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Frontiers of Medicine 2018年第4期12卷 451-462页

作者： Xiao-Dong Yang Shao-Cong Sun Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai 200025 China Department of Immunology The University of Texas MD Anderson Cancer Center 7455 Fannin Street Box 902 Houston TX 77030 USA The University of Texas Graduate School of Biomedical Sciences at Houston Houston TX 77030 USA

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases （DUBs）. DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

关键词： deubiquitinase ubiquitination T cell activation T cell differentiation T cell tolerance

TRAF2 regulates T cell immunity by maintaining a Tpl2-ERK survival signaling axis in effector and memory CD8 T cells

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Cellular & Molecular Immunology 2021年第9期18卷 2262-2274页

作者： Xiaoping Xie Lele Zhu Zuliang Jie Yanchuan Li Meidi Gu Xiaofei Zhou Hui Wang Jae-Hoon Chang Chun-Jung Ko Xuhong Cheng Shao-Cong Sun Department of Immunology The University of Texas MD Anderson Cancer Center7455 Fannin StreetBox 902HoustonTX77030USA Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyXuzhou Medical University209 Tongshan RoadXuzhou221004JiangsuChina College of Pharmacy Yeungnam UniversityGyeongsan712-749Republic of Korea MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences HoustonTX77030USA

Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against *** show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against *** signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor *** mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor ***,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell ***,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.

关键词： T cell survival Effector and memory CD8 T cells Protective immunity Bacterial infection TRAF2 NIK Tpl2

Testosterone and metabolic syndrome

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Asian Journal of Andrology 2015年第2期17卷 192-196,I0006页

作者： Glenn R Cunningham Departments of Medicine and Molecular and Cellular Biology Baylor College of Medicine Baylor St. Luke's Medical Center 6624 Fannin Suite 1180 Houston TX 77030 USA.

Controversies surround the usefulness of identifying patients with the metabolic syndrome （MetS）. Many of the components are accepted risk factors for cardiovascular disease （CVD）. Although the MetS as defined includes many men with insulin resistance, insulin resistance is not universal. The low total testosterone （TT） and sex hormone binding globulin （SHBG） levels in these men are best explained by the hyperinsulinism and increased inflammatory cytokines that accompany obesity and increased waist circumference. It is informative that low SHBG levels predict future development of the MetS. Evidence is strong relating low TT levels to CVD in men with and without the MetS; however, the relationship may not be causal. The recommendations of the International Diabetes Federation for managing the MetS include cardiovascular risk assessment, lifestyle changes in diet, exercise, weight reduction and treatment of individual components of the MetS. Unfortunately, it is uncommon to see patients with the MetS lose and maintain a 10% weight loss. Recent reports showing testosterone treatment induced dramatic changes in weight, waist circumference, insulin sensitivity, hemoglobin Alc levels and improvements in each of the components of the MetS are intriguing. While some observational studies have reported that testosterone replacement therapy increases cardiovascular events, the Food and Drug Administration in the United States has reviewed these reports and found them to be seriously flawed. Large, randomized, placebo-controlled trials are needed to provide more definitive data regarding the efficacy and safety of this treatment in middle and older men with the MetS and low TT levels.

关键词： cardiovascular risk metabolic syndrome sex hormone binding globulin testosterone testosterone replacement therapy

Innovative treatments for congenital heart defects

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World Journal of Pediatrics 2023年第1期19卷 1-6页

作者： Antonio F.Corno Taylor S.Koerner Jorge D.Salazar McGovern Medical School Children's Heart InstituteMemorial Hermann Children's HospitalUniversity of Texas Health Science Center in Houston6410 Fannin StreetMSB 6.274HoustonTX 77030USA

The past few decades have witnessed substantial advances in the treatment of complex congenital heart defects,with most significant advances in surgical treatment strategies and improved outcomes dependent upon well-educated and calculated risk-taking *** the present surgical era,doing nothing for complex congenital heart defects is unacceptable,and pioneering surgeons are willing to under-take and accept the substantial risks of innovative pediatric cardiac surgery[1].

关键词： congenital treatment defects

Deep brain stimulation in Parkinson’s disease

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Translational Neurodegeneration 2013年第1期2卷 154-163页

作者： Raja Mehanna Eugene C Lai UT Move University of Texas Health Care Science CenterHoustonTXUSA Department of Neurology Houston Methodist Neurological Institute6560 FanninSuite 802Houston 77030TXUSA

For the last 50 years,levodopa has been the cornerstone of Parkinson’s disease ***,a majority of patients develop motor complications a few years after therapy *** brain stimulation has been approved by the FDA as an adjunctive treatment in Parkinson disease,especially aimed at controlling these ***,the exact mechanism of action of deep brain stimulation,the best nucleus to target as well as the best timing for surgery are still *** here provide an in-depth and critical review of the current literature on this topic.

关键词： Deep brain stimulation Parkinson’s disease Subthalamic nucleus Globus pallidus