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ABSTRACT: E3 ubiquitin ligases play a crucial role in regulating immune receptor signaling and modulating immune homeostasis and activation. One emerging family of such E3s is the Pelle-interacting (Peli) proteins, characterized by the presence of a cryptic forkhead-associated domain involved in substrate binding and an atypical RING domain mediating formation of both lysine (K) 63- and K48-linked polyubiquitin chains. A well-recognized function of Peli family members is participation in the signal transduction mediated by Toll-like receptors (TLRs) and IL-1 receptor. Recent gene targeting studies have provided important insights into the in vivo functions of Peli1 in the regulation of TLR signaling and inflammation. These studies have also extended the biological functions of Peli1 to the regulation of T-cell tolerance. Consistent with its immunoregulatory functions, Peli1 responds to different immune stimuli for its gene expression and catalytic activation. In this review, we discuss the recent progress, as well as the historical perspectives in the regulation and biological functions of Peli.
Cellular & molecular immunology 03/2012; 9(2):113-22. · 2.99 Impact Factor
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Mikyoung Chang, Wei Jin,
Jae-Hoon Chang,
Yichuan Xiao,
George C Brittain,
Jiayi Yu,
Xiaofei Zhou,
Yi-Hong Wang,
Xuhong Cheng,
Pingwei Li,
Brian A Rabinovich,
Patrick Hwu,
Shao-Cong Sun
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ABSTRACT: T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-β (TGF-β). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.
Nature Immunology 08/2011; 12(10):1002-9. · 26.01 Impact Factor
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ABSTRACT: Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on both T-cell intrinsic factors and the supporting function of B cells, but the underlying molecular mechanisms are incompletely understood. Here we show that NF-κB-inducing kinase (NIK), a central component of the noncanonical NF-κB signaling pathway, is required for Tfh cell development. Unlike other known Tfh regulators, NIK acts by controlling the supporting function of B cells. NIK and its upstream BAFF receptor regulate B-cell expression of inducible costimulator ligand (ICOSL), a molecule required for Tfh cell generation. Consistently, injection of a recombinant ICOSL protein into NIK-deficient mice largely rescues their defect in Tfh cell development. We provide biochemical and genetic evidence indicating that the ICOSL gene is a specific target of the noncanonical NF-κB. Our findings suggest that the noncanonical NF-κB pathway regulates the development of Tfh cells by mediating ICOSL gene expression in B cells.
Proceedings of the National Academy of Sciences 08/2011; 108(31):12827-32. · 9.68 Impact Factor
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Bailu Peng,
Jianhua Ling,
Andrew Joon Lee,
Zilai Wang,
Zhe Chang, Wei Jin,
Ya'an Kang,
Richard Zhang,
David Shim,
Huamin Wang,
Jason B Fleming,
Hui Zheng,
Shao-Cong Sun,
Paul J Chiao
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ABSTRACT: Feedback regulation of transcription factor NF-kappaB by its inhibitor IkappaBalpha plays an essential role in control of NF-kappaB activity. To understand the biological significance of IkappaBalpha-mediated feedback regulation of NF-kappaB, we generated mice harboring mutated kappaB enhancers in the promoter of the IkappaBalpha gene (IkappaBalpha(M/M)) to inhibit NF-kappaB-regulated IkappaBalpha expression. Here, we report that these mutant mice are defective in NF-kappaB-induced expression of IkappaBalpha. This defective feedback regulation of NF-kappaB by IkappaBalpha not only altered activity of NF-kappaB, but also the expression of NF-kappaB-regulated genes. As a result, IkappaBalpha(M/M), the homozygous knock-in mice with mutated kappaB enhancers in the IkappaBalpha promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sjögren's Syndrome. These findings therefore demonstrate that the IkappaBalpha-mediated feedback regulation of NF-kappaB has an essential role in controlling T-cell development and functions, provide mechanistic insight into the development of Sjögren's Syndrome, and suggest the potential of NF-kappaB signaling as a therapeutic target for Sjögren's Syndrome and other autoimmune diseases.
Proceedings of the National Academy of Sciences 08/2010; 107(34):15193-8. · 9.68 Impact Factor
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Bailu Peng,
Jianhua Ling,
Andrew Joon Lee,
Zilai Wang,
Zhe Chang, Wei Jin,
Ya'an Kang,
Richard Zhang,
David Shim,
Huamin Wang,
Jason B. Fleming,
Hui Zheng,
Shao-Cong Sun,
Paul J. Chiao
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ABSTRACT: Feedback regulation of transcription factor NF-κB by its inhibitor IκBα plays an essential role in control of NF-κB activity.
To understand the biological significance of IκBα-mediated feedback regulation of NF-κB, we generated mice harboring mutated
κB enhancers in the promoter of the IκBα gene (IκBαM/M) to inhibit NF-κB–regulated IκBα expression. Here, we report that these mutant mice are defective in NF-κB–induced expression
of IκBα. This defective feedback regulation of NF-κB by IκBα not only altered activity of NF-κB, but also the expression of
NF-κB–regulated genes. As a result, IκBαM/M, the homozygous knock-in mice with mutated κB enhancers in the IκBα promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sjögren’s Syndrome. These findings therefore demonstrate that the IκBα-mediated feedback regulation of NF-κB has an essential role
in controlling T-cell development and functions, provide mechanistic insight into the development of Sjögren’s Syndrome, and suggest the potential of NF-κB signaling as a therapeutic target for Sjögren’s Syndrome and other autoimmune diseases.
Proceedings of the National Academy of Sciences 08/2010; 107(34):15193-15198. · 9.68 Impact Factor
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Roza I Nurieva,
Shuling Zheng, Wei Jin,
Yeonseok Chung,
Yongliang Zhang,
Gustavo J Martinez,
Joseph M Reynolds,
Sung-Ling Wang,
Xin Lin,
Shao-Cong Sun,
Guillermina Lozano,
Chen Dong
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ABSTRACT: T cell activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (GRAIL, encoded by Rnf128) is an E3 ubiquitin ligase associated with T cell tolerance. Here, we generated and analyzed GRAIL-deficient mice and found they were resistant to immune tolerance induction and exhibited greater susceptibility to autoimmune diseases than wild-type mice. GRAIL-deficient naive T cells, after activation, exhibited increased proliferation and cytokine expression than controls and did not depend on costimulation for effector generation. Moreover, GRAIL-deficient regulatory T (Treg) cells displayed reduced suppressive function, associated with increased Th17 cell-related gene expression. GRAIL-deficient naive and Treg cells were less efficient in downregulating T cell receptor (TCR)-CD3 expression after activation and exhibited increased NFATc1 transcription factor expression; GRAIL expression promoted CD3 ubiquitinylation. Our results indicate that GRAIL, by mediating TCR-CD3 degradation, regulates naive T cell tolerance induction and Treg cell function.
Immunity 05/2010; 32(5):670-80. · 21.64 Impact Factor
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ABSTRACT: Toll-like receptors (TLRs) are pivotal in innate immunity and inflammation. Here we show that genetic deficiency in Peli1, an E3 ubiquitin ligase, attenuated the induction of proinflammatory cytokines by ligands of TLR3 and TLR4 and rendered mice resistant to septic shock. Peli1 was required for TLR3-induced activation of IkappaB kinase (IKK) and its 'downstream' target, transcription factor NF-kappaB, but was dispensable for IKK-NF-kappaB activation induced by several other TLRs and the interleukin 1 (IL-1) receptor. Notably, Peli1 bound to and ubiquitinated RIP1, a signaling molecule that mediates IKK activation induced by the TLR3 and TLR4 adaptor TRIF. Our findings suggest that Peli1 is a ubiquitin ligase needed for the transmission of TRIF-dependent TLR signals.
Nature Immunology 10/2009; 10(10):1089-95. · 26.01 Impact Factor
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ABSTRACT: Th17 cells play an important role in mediating autoimmune diseases, but the molecular mechanism underlying Th17 differentiation is incompletely understood. We show here that NF-kappaB-inducing kinase (NIK), which is known to regulate B-cell maturation and lymphoid organogenesis, is important for the induction of Th17 cells. NIK-deficient naive CD4 T cells are attenuated in the differentiation to Th17 cells, although they are competent in committing to the other effector lineages. Consistently, NIK knockout mice are resistant to experimental autoimmune encephalomyelitis, a disease model that involves the function of Th17 cells. This phenotype was also detected in Rag2 knockout mice reconstituted with NIK-deficient T cells, confirming a T-cell intrinsic defect. We further show that NIK mediates synergistic activation of STAT3 by T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates activation of STAT3 and induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and experimental autoimmune encephalitis induction.
Blood 06/2009; 113(26):6603-10. · 9.90 Impact Factor
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ABSTRACT: Lithium is an anti-depressant drug that also possesses immunomodulatory functions. The anti-inflammatory effect of lithium is thought to involve activation of the transcription factor CREB, although the underlying mechanism is incompletely understood. We show here that in macrophages lithium stimulates Tpl2, a MAP kinase kinase kinase (MAP3K) known to mediate activation of extracellular signal regulated kinase (ERK) and the downstream target CREB. Lithium activates Tpl2 by inducing degradation of p105, an NF-kappaB precursor protein that functions as a physiological inhibitor of Tpl2. This novel function of lithium does not involve inhibition of a well-characterized lithium target, GSK3beta, since other known GSK3beta inhibitors do not induce p105 degradation or Tpl2 activation. Lithium also promotes the activation of Tpl2 and ERK by the TLR4 ligand LPS. On the other hand, prolonged incubation of macrophages with lithium results in dramatic loss of p105 and inhibition of LPS-stimulated NF-kappaB activation. Consequently, lithium both attenuates LPS-mediated pro-inflammatory gene induction and induces apoptosis in macrophages. These results provide novel insight into the anti-inflammatory function of lithium.
Cellular signalling 01/2009; 21(4):559-66. · 4.09 Impact Factor
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ABSTRACT: The IkappaB kinase (IKK)-related kinases, IKKepsilon and TBK1, participate in the induction of type I interferons (IFNs) during viral infections. Deregulated activation of IKKepsilon and TBK1 also contributes to the abnormal cell survival and transformation. However, how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role in preventing aberrant activation of IKKepsilon/TBK1. CYLD deficiency causes constitutive activation of IKKepsilon/TBK1, which is associated with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKKepsilon/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function, CYLD potently inhibits RIG-I-mediated activation of the IFN-beta promoter. These findings establish CYLD as a key negative regulator of IKKepsilon/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.
Journal of Biological Chemistry 08/2008; 283(27):18621-6. · 4.77 Impact Factor
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ABSTRACT: The IκB kinase (IKK)-related kinases, IKKϵ and TBK1, participate in the induction of type I interferons (IFNs) during viral
infections. Deregulated activation of IKKϵ and TBK1 also contributes to the abnormal cell survival and transformation. However,
how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role
in preventing aberrant activation of IKKϵ/TBK1. CYLD deficiency causes constitutive activation of IKKϵ/TBK1, which is associated
with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and
inhibits the ubiquitination of this IKKϵ/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function,
CYLD potently inhibits RIG-I-mediated activation of the IFN-β promoter. These findings establish CYLD as a key negative regulator
of IKKϵ/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.
Journal of Biological Chemistry 07/2008; 283(27):18621-18626. · 4.77 Impact Factor
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ABSTRACT: Osteoclastogenesis is a tightly regulated biological process, and deregulation can lead to severe bone disorders such as osteoporosis. The regulation of osteoclastic signaling is incompletely understood, but ubiquitination of TNF receptor-associated factor 6 (TRAF6) has recently been shown to be important in mediating this process. We therefore investigated the role of the recently identified deubiquitinating enzyme CYLD in osteoclastogenesis and found that mice with a genetic deficiency of CYLD had aberrant osteoclast differentiation and developed severe osteoporosis. Cultured osteoclast precursors derived from CYLD-deficient mice were hyperresponsive to RANKL-induced differentiation and produced more and larger osteoclasts than did controls upon stimulation. We assessed the expression pattern of CYLD and found that it was drastically upregulated during RANKL-induced differentiation of preosteoclasts. Furthermore, CYLD negatively regulated RANK signaling by inhibiting TRAF6 ubiquitination and activation of downstream signaling events. Interestingly, we found that CYLD interacted physically with the signaling adaptor p62 and thereby was recruited to TRAF6. These findings establish CYLD as a crucial negative regulator of osteoclastogenesis and suggest its involvement in the p62/TRAF6 signaling axis.
Journal of Clinical Investigation 06/2008; 118(5):1858-66. · 15.39 Impact Factor
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ABSTRACT: Spermatogenesis involves an early wave of germ cell apoptosis, which is required for maintaining the balance between germ cells and supporting Sertoli cells. However, the signaling mechanism regulating this apoptotic event is poorly defined. Here we show that genetic deficiency of Cyld, a recently identified deubiquitinating enzyme, attenuates the early wave of germ cell apoptosis and causes impaired spermatogenesis in mice. Interestingly, the loss of CYLD in testicular cells leads to activation of the transcription factor NF-kappaB and aberrant expression of antiapoptotic genes. We further show that CYLD negatively regulates a ubiquitin-dependent NF-kappaB activator, RIP1. CYLD binds to RIP1 and inhibits its ubiquitination and signaling function. These findings establish CYLD as a pivotal deubiquitinating enzyme (DUB) that regulates germ cell apoptosis and spermatogenesis and suggest an essential role for CYLD in controlling the RIP1/NF-kappaB signaling axis in testis.
Developmental Cell 12/2007; 13(5):705-16. · 14.03 Impact Factor
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William W Reiley, Wei Jin,
Andrew Joon Lee,
Ato Wright,
Xuefeng Wu,
Eric F Tewalt,
Timothy O Leonard,
Christopher C Norbury,
Leo Fitzpatrick,
Minying Zhang,
Shao-Cong Sun
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ABSTRACT: The deubiquitinating enzyme CYLD has recently been implicated in the regulation of signal transduction, but its physiological function and mechanism of action are still elusive. In this study, we show that CYLD plays a pivotal role in regulating T cell activation and homeostasis. T cells derived from Cyld knockout mice display a hyperresponsive phenotype and mediate the spontaneous development of intestinal inflammation. Interestingly, CYLD targets a ubiquitin-dependent kinase, transforming growth factor-beta-activated kinase 1 (Tak1), and inhibits its ubiquitination and autoactivation. Cyld-deficient T cells exhibit constitutively active Tak1 and its downstream kinases c-Jun N-terminal kinase and IkappaB kinase beta. These results emphasize a critical role for CYLD in preventing spontaneous activation of the Tak1 axis of T cell signaling and, thereby, maintaining normal T cell function.
Journal of Experimental Medicine 07/2007; 204(6):1475-85. · 13.85 Impact Factor
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ABSTRACT: Deubiquitinating enzymes (DUB) form a family of cysteine proteases that digests ubiquitin chains and reverses the process of protein ubiquitination. Despite the identification of a large number of DUBs, their physiological functions remain poorly defined. Here we provide genetic evidence that CYLD, a recently identified DUB, plays a crucial role in regulating the peripheral development and activation of B cells. Disruption of the CYLD gene in mice results in B cell hyperplasia and lymphoid organ enlargement. The CYLD-deficient B cells display surface markers indicative of spontaneous activation and are hyperproliferative upon in vitro stimulation. When challenged with antigens, the CYLD(-/-) mice develop exacerbated lymphoid organ abnormalities and abnormal B cell responses. Although the loss of CYLD has only a minor effect on B cell development in bone marrow, this genetic deficiency disrupts the balance of peripheral B cell populations with a significant increase in marginal zone B cells. In keeping with these functional abnormalities, the CYLD(-/-) B cells exhibit constitutive activation of the transcription factor NF-kappaB due to spontaneous activation of IkappaB kinase beta and degradation of the NF-kappaB inhibitor IkappaBalpha. These findings demonstrate a critical role for CYLD in regulating the basal activity of NF-kappaB and maintaining the naive phenotype and proper activation of B cells.
Journal of Biological Chemistry 05/2007; 282(21):15884-93. · 4.77 Impact Factor
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ABSTRACT: T cell receptor signaling is essential for the generation and maturation of T lymphocyte precursors. Here we identify the deubiquitinating enzyme CYLD as a positive regulator of proximal T cell receptor signaling in thymocytes. CYLD physically interacted with active Lck and promoted recruitment of active Lck to its substrate, Zap70. CYLD also removed both Lys 48- and Lys 63-linked polyubiquitin chains from Lck. Because of a cell-autonomous defect in T cell development, CYLD-deficient mice had substantially fewer mature CD4(+) and CD8(+) single-positive thymocytes and peripheral T cells.
Nature Immunology 05/2006; 7(4):411-7. · 26.01 Impact Factor
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ABSTRACT: The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS). In response to LPS stimulation, Tpl2 phosphorylates a downstream kinase, MEK1, leading to the activation of ERK signaling pathway. Recent studies demonstrate that the NF-kappaB1 precursor protein p105 functions as an inhibitor of Tpl2 and that the LPS-stimulated Tpl2 activation requires p105 degradation. However, how p105 inhibits the signaling function of Tpl2 is not completely understood. We show here that p105 does not inhibit the intrinsic kinase activity of Tpl2. When complexed with p105, Tpl2 remains catalytically active and uses p105 as a substrate. However, the p105-bound Tpl2 is unable to phosphorylate its physiological target, MEK1. These findings suggest that p105 functions as a competitive inhibitor of Tpl2 that blocks its access by MEK1.
Biochimica et Biophysica Acta 03/2006; 1763(2):174-81. · 4.66 Impact Factor
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ABSTRACT: IkappaB kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-kappaB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKbeta, but not IKKalpha, is required for Tpl2 activation. Moreover, this novel function of IKKbeta appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-kappaB1/p105. These findings suggest that IKKbeta exerts its immune-regulatory functions by targeting different downstream signaling pathways.
Molecular and Cellular Biology 08/2004; 24(13):6040-8. · 5.53 Impact Factor
