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Negative Regulation of Cytokine Signaling in Immunity

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Negative Regulation of Cytokine Signaling in Immunity Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Negative Regulation of Cytokine Signaling in Immunity Akihiko Yoshimura, Minako Ito, Shunsuke Chikuma, Takashi Akanuma, and Hiroko Nakatsukasa Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan Correspondence: [email protected] Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene tran- scriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4þ T cells and the maturation of CD8þ T cells. SOCS proteins also regulate innate immune cells and are involved in tumorigenesis. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in T cells and tumor immunity. here are four types of the cytokine receptors: (ERK) pathway (see Fig. 1). Any receptor that T(1) receptors that activate nuclear factor activates intracellular signaling pathways has (NF)-kB and mitogen-activated protein (MAP) multiple negative feedback systems, which en- kinases (mainly p38 and c-Jun amino-terminal sures transient activation of the pathway and kinase [JNK]), such as receptors for the tumor downstream transcription factors. Typical neg- necrosis factor (TNF)-a family, the interleukin ative regulators are shown in Figure 1. Lack of (IL)-1 family, including IL-1b, IL-18, and IL- such negative regulators results in autoimmune 33, and the IL-17 family; (2) receptors that diseases, autoinflammatory diseases, and some- activate the Janus kinase and signal transducers times-fatal disorders, including cancer. Thus, and activators of transcription (JAK-STAT) negative feedback is essential for homeostasis. pathway—most cytokines belong to this family; Cytokine receptor signal regulators can (3) transforming growth factor (TGF)-b recep- be classified into three types: (1) proteins that tors carrying a serine/threonine kinase that physically suppress signal generation, (2) pro- activates Smad-family transcription factors; tein phosphatases, and (3) proteins recruiting and (4) growth factor receptors in which cyto- degradation systems or processes such as pro- plasmic domain contains the tyrosine kinase teasomes, autophagy, and endocytosis. All are domain. This latter family typically signals via multidomain proteins that bind to the receptors the Ras extracellular signal-regulated kinase and/or signaling molecules through an Src ho- Editors: Warren J. Leonard and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028571 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028571 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press A. Yoshimura et al. IL-6 TGF-β TNF IL6R/gp130 FGF JAK1 JAK1 TRADD FGFR TRADD TNFR TRAF2 FADD R-Smad Ras P STAT I-Smad Raf P A-20 Spred SOCS/CIS IKK complex Co-Smad MAP kinase κ I B IκB NF-κB P P Figure 1. The cytokine signaling and their major negative regulators. There are four types of cytokine receptors: (1) receptors that activate nuclear factor (NF)-kB and mitogen-activated protein (MAP) kinases; (2) receptors that activate the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway; (3) transforming growth factor (TGF)-b receptors; and (4) growth factor receptor family. Typical negative regulators are also shown. TNF, Tumor necrosis factor; TNFR, TNF receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; IKK, IkB kinase; SOCS/CIS, suppressor of cytokine signaling/cytokine-inducible Src homology 2 (SH2)-containing protein; Spred, Sprouty-related protein with an EVH1 domain. mology 2 (SH2) domain or other binding minal SOCS-box that recruits the ubiquitin- motifs and then suppress the signaling via other transferase complex. Because of space limita- domains. For example, A20/TNFAIP3 is an tions in this review, we focus on proteins, espe- important negative regulatory protein for the cially SOCS proteins, which regulate signal NF-kB pathway that interacts with NF-kB es- transduction, but not on molecules interacting sential modulator (NEMO)/IkB kinase (IKK)g with the extracellular domain of the receptors or and functions as a deubiquitinase (Shembade on transcription factors. and Harhaj 2012). Sprouty-related protein with an EVH1 domain (Spred) family proteins THE JAK-STAT PATHWAY suppress the Ras-ERK pathway by bridging the growth factor/cytokine receptors and NF-1, a Cytokines play several essential roles in the Ras-GTPase-activating protein (Wakioka et al. development, differentiation, and function of 2001; Nonami et al. 2003; Yoshida et al. 2006; myeloid and lymphoid cells. Some of them, Hirata et al. 2016). Some negative-regulator including ILs, interferons (IFNs), and hemato- proteins have two or more inhibitory domains; poietic growth factors, activate the JAK-STAT for example, suppressor of cytokine signaling pathway (O’Shea et al. 2002). In this pathway, (SOCS)1 and SOCS3 have an amino-terminal cytokine binding results in receptor oligomeri- kinase-inhibitory region (KIR) that inhibits zation, which initiates the activation of JAK JAK tyrosine kinase activity and a carboxy-ter- kinases (JAK1, JAK2, JAK3, and TYK2). JAK3 2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028571 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Negative Regulation of Cytokine Signaling in Immunity is associated with IL-2 receptor g (common for Th1, Th2, and Th17 differentiation, respec- cytokine receptor g chain), and is activated tively. IL-4 in combination with TGF-b has by IL-2-related cytokines. The activated JAKs been shown to induce Th9 in vitro (Tamiya phosphorylate the receptor cytoplasmic do- et al. 2013). IL-2/STAT5 is essential for regula- mains, which creates docking sites for SH2-con- tory T-cell (Treg) development, and IL-21/ taining signaling proteins. The STAT proteins STAT3 is essential for follicular helper T (Tfh) are the major substrates for JAKs. A large num- cell differentiation (Vogelzang et al. 2008). IL- ber of cytokines, growth factors, and hormonal 21 also regulates CD8þ T cells (Gagnon et al. factors activate the JAK-STAT pathway. For 2007) and Th17 cell differentiation (Bettelli example, IFN-g receptors activate JAK1 and et al. 2007). JAK2, which then mainly phosphorylate and activate STAT1, whereas IL-6 binds to the IL-6 THE CIS/SOCS FAMILY: MOLECULAR receptor a (IL-6Ra) chain and to gp130, both MECHANISMS of which mainly activate JAK1 and STAT3 (Gu- schin et al. 1995). The anti-inflammatory cyto- SOCS proteins and cytokine-inducible SH2- kine IL-10 also activates STAT3 (Weber-Nordt containing protein ([CIS] also known as CISH) et al. 1996). T helper (Th)1, Th2, and Th17 are molecules comprise a family of intracellular induced by IL-12, IL-4, and IL-6/IL-23, and proteins (Fig. 2) (Yoshimura et al. 1995, 2007; thus STAT4, STAT6, and STAT3 are essential Endo et al. 1997; Matsumoto et al. 1997; Tamiya CIS/SOCS family genes Cytokine Cytokine Name Structure Receptor SH2 SOCS-box CIS1 JAB/SSI1/SOCS1 JAK JAK JAK JAK P P P CIS2/SSI2/SOCS2 P P SOCS3 P SOCS1 CIS3/SSI3/SOCS3 P P P STAT STAT CIS1 CIS4/SOCS6 STAT5 CIS6/NAP4/SOCS7 CIS6/SOCS5 P P CIS7/SOCS4 SOCS3/CIS3 CIS1 SOCS-box-containing genes SOCS/JAB ASB WSB Rar P Transcription VHL P Figure 2. Structure and function of the suppressor of cytokine signaling (SOCS) family. The SOCS family consists of eight family members. All eight members share a central Src homology 2 (SH2) domain and a carboxy-terminal SOCS box. In addition, SOCS1 and SOCS3 possess a kinase inhibitory region (KIR) that inhibits Janus kinase (JAK) activity. (Right) The general mechanism of the action of cytokine-inducible SH2- containing protein (CIS), SOCS1, and SOCS3. STAT, Signal transducers and activators of transcription; JAB, Janus kinase-binding protein. Cite this article as Cold Spring Harb Perspect Biol 2018;10:a028571 3 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press A. Yoshimura et al. et al. 2011). There are eight CIS/SOCS family their KIR. KIR has been proposed to function proteins: CIS, SOCS1, SOCS2, SOCS3, SOCS4, as a pseudosubstrate, and it is essential for SOCS5, SOCS6, and SOCS7, each of which the suppression of cytokine signals (Fig. 2) has a central SH2 domain, an amino-terminal (Yasukawa et al. 1999; Kershaw et al. 2013). domain of variable length and sequence, and Recent study of the ternary cocrystal structure a carboxy-terminal 40-amino-acid module between mouse SOCS3, JAK2 kinase domain, known as the SOCS box (Fig. 2) (Hilton et al. and a fragment of gp130 supported this hypoth- 1998; Kamizono et al. 2001; Kamura et al. esis (Fig. 3). The kinase-inhibitory region of 2004). The SOCS box interacts with elongin SOCS3 occludes the substrate-binding groove B/C, Cullins, and the Really Interesting New on JAK2, and biochemical studies show that it Gene (RING)-finger domain-only protein blocks substrate association. SOCS3, and prob- RBX2, which recruits E2 ubiquitin transferase ably SOCS1, inhibits the catalytic activity of (Kamura et al. 2004). CIS/SOCS family pro- JAK1, JAK2, and TYK2, but not JAK3, because teins, as well as other SOCS-box-containing the SH2-KIR domain interacts with an evolu- molecules, function as E3 ubiquitin ligases tionarily conserved “GQM” sequence that is and mediate the degradation of proteins that present in all vertebrate forms of JAK1, JAK2, are associated with these family members and TYK2, but not JAK3, where it lines one edge through their amino-terminal regions (Fig.
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