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Dephosphorylating TRAM TRIF-Dependent TLR4 Pathway by Phosphatase PTPN4 Preferentially Inhibits

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Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM This information is current as Wanwan Huai, Hui Song, Lijuan Wang, Bingqing Li, Jing of September 29, 2021. Zhao, Lihui Han, Chengjiang Gao, Guosheng Jiang, Lining Zhang and Wei Zhao J Immunol published online 30 March 2015 http://www.jimmunol.org/content/early/2015/03/28/jimmun ol.1402183 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 30, 2015, doi:10.4049/jimmunol.1402183 The Journal of Immunology Phosphatase PTPN4 Preferentially Inhibits TRIF-Dependent TLR4 Pathway by Dephosphorylating TRAM Wanwan Huai,* Hui Song,* Lijuan Wang,† Bingqing Li,‡ Jing Zhao,* Lihui Han,* Chengjiang Gao,* Guosheng Jiang,‡ Lining Zhang,* and Wei Zhao* TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. However, the mechanisms by which TRAM links downstream molecules are not fully elucidated. In this study, we show that TRAM undergoes tyrosine phosphorylation upon TLR4 activation and that is required for TLR4-induced IRF3 activation. Protein tyrosine phosphatase nonreceptor type 4 (PTPN4), a protein tyrosine phosphatase, inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRAM, resulting in the disturbance of TRAM–TRIF interaction. Consequently, PTPN4 specifically inhibits TRIF-dependent IRF3 activation and IFN-b production in TLR4 pathway. Therefore, our results provide new insight into the TLR4 pathway and identify PTPN4 as a specific Downloaded from inhibitor of TRIF-dependent TLR4 pathway. Targeting PTPN4 would be beneficial for the development of new strategy to control TLR4-associated diseases without unwanted side effects. The Journal of Immunology, 2015, 194: 000–000. attern recognition receptors (PRRs) mediate the recogni- IRF3 and then induces the expression of type I IFN (IFN-a/b)(3). tion of pathogen-associated molecular patterns and trigger BesidesTLR4,TLR3alsousesTRIFtoactivatedownstream http://www.jimmunol.org/ P innate immune responses against pathogens invasion (1, 2). pathways, while it recruits TRIF directly, without the need for TLRs are the best characterized PRRs, which possess leucine- TRAM. rich repeats, transmembrane domains, and intracellular Toll-IL-1R Reversible phosphorylation of proteins, which is catalyzed by (TIR) domains (2, 3). Unique among the large family of TLRs, kinases and phosphatases, is a key regulatory mechanism for nu- TLR4 engages two distinct adaptor proteins: MyD88 and TRIF, merous important aspects of physiology. Phosphorylation status of which activates two separate pathways, the MyD88-dependent and receptors or adaptors involved in PRRs signaling directly affects TRIF-dependent pathway (also called MyD88-independent path- the transduction of activation signals and is crucial for optimal ways) (3). In the case of TLR4 signaling, TLR4 uses two adaptors: innate immune responses. For example, a dynamic balance be- TIR domain–containing adapter protein (TIRAP, also known as tween phosphorylation and dephosphorylation of RIG-I and MDA5 by guest on September 29, 2021 Mal) and TRIF-related adaptor molecule (TRAM, also known as is essential for their signal transduction (9). Serine phosphorylation TICAM2) as sorting adaptors to facilitate signal transduction (3). of NLRC4 (a cytosolic member of the NOD-like receptor family) TIRAP recruits MyD88 to facilitate the activation of the MyD88- is critical for inflammasome activation (10). In the setting of TLR dependent pathway at the plasma membrane, resulting in the ac- pathways, TLR2, TLR3, TLR4, TLR5, TLR8, and TLR9 undergo tivation of NF-kB and MAPK pathways, and subsequent secretion tyrosine phosphorylation (11), and mutations of tyrosines within of proinflammatory cytokines, such as TNF-a and IL-6. As for the their TIR domains suppress TLRs activation. In addition to the TRIF-dependent pathway, TRAM is needed for the recruitment of receptors, other components of the PRRs signaling pathways (e.g., TRIF (4–6). Following LPS stimulation, TRAM dissociate from the adaptors, also undergo tyrosine phosphorylation upon ligand the membrane to endosomes, where the TRAM–TRIF pathway is engagement) (11). Tyrosine phosphorylation of TIRAP is required initiated (7, 8). This leads to the activation of transcription factor for the recruitment of MyD88 to TLR2 and TLR4 (12, 13). TRIF and MyD88 have been shown to be tyrosine phosphorylated *Department of Immunology, Shandong University School of Medicine, Jinan, Shan- causing downregulation of TLR signaling (14). However, the dong 250012, China; †Pathology Tissue Bank, Qilu Hospital, Shandong University, phosphorylation modification of key proteins in PRRs signaling Jinan, Shandong 250012, China; and ‡Institute of Basic Medicine, Shandong Acad- emy of Medical Sciences, Jinan, Shandong 250062, China has not been fully elucidated. Protein tyrosine phosphatases Received for publication August 25, 2014. Accepted for publication February 18, (PTPs), which dephosphorylate tyrosine residues of target sub- 2015. strates (15, 16), have been reported to be involved in the regulation This work was supported by grants from the National Natural Science Foundation of of innate immune responses, such as Src homology region 2 do- China (Grant 31370017), Shandong Provincial Nature Science Foundation for Dis- main–containing phosphatase-1 (17), Src homology region 2 do- tinguished Young Scholars (Grant JQ201420), and the National “973” Program of China (Grant 2011CB503906). main–containing phosphatase-2 (18), PTPN22 (19), PTP with Address correspondence and reprint requests to Dr. Wei Zhao, Department of Immu- proline-glutamine-serine-threonine-rich motifs (20), PTP1B (21), nology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong, and so on. However, the PTPs identified to be PRRs regulators 250012, China. E-mail address: [email protected]. possessed broadly regulatory effects and that limited their poten- Abbreviations used in this article: HA, hemagglutinin; HEK, human embryonic tial implication for immunotherapy. Thus, more specific regulator kidney; IP, immunoprecipitation; LTA, lipothechoic acid; PGN, peptidoglycan; poly(I:C), polyinosinic:polycytidylic acid; PRR, pattern recognition receptor; remains to be identified. PTPN4, protein tyrosine phosphatase nonreceptor type 4; SeV, Sendai virus; PTP nonreceptor type 4 (PTPN4, also known as PTP-MEG1) TAG, TRAM adaptor with GOLD; TIR, Toll-IL 1R; TIRAP, TIR domain–containing functions in TCR cell signaling and apoptosis (22, 23). How- adapter protein; TRAM, TRIF-related adaptor molecule; WT, wild-type. ever, to our knowledge, the roles of PTPN4 in innate immune Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 responses have never been investigated. In this study, we show that www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402183 2 PTPN4 INHIBITS TRAM TYROSINE PHOSPHORYLATION PTPN4 specifically inhibits TRIF-dependent TLR4 pathway by GGAUUUGUUAAACCAUUAA-39 (siRNA 1) and 59-GGUUUGGAUUC- suppressing tyrosine phosphorylation of TRAM. TRAM under- AAUGUAAA-39 (siRNA 2) for PTPN4, and “scrambled” control sequences 9 9 goes tyrosine phosphorylation at Tyr167 upon TLR4 activation were 5 -UUCUCCGAACGUGUCACGU-3 . siRNA sequences for TRIM38 were described previously (25). and that is required for TLR4-induced IRF3 activation and IFN-b secretion. PTPN4 attenuates TRAM tyrosine phosphorylation and ELISA inhibits its translocation and subsequent TRAM–TRIF interaction. The concentration of IFN-b was measured with ELISA kits (BioLegend, These results indicate that tyrosine phosphorylation of TRAM is San Diego, CA). The concentrations of TNF-a and IL-6 were measured critical for TLR4 activation and also identify PTPN4 as a specific with ELISA kits (Dakewe Biotech, Shenzhen, China). inhibitor of TRIF-dependent pathway triggered by TLR4 en- RNA quantitation gagement. Total RNA was extracted with TRIzol reagent, according to the manu- facturer’s instructions (Invitrogen). A LightCycler (ABI PRISM 7000) and Materials and Methods a SYBR RT-PCR kit (Takara) were used for quantitative real-time RT-PCR 9 Mice and reagents analysis. Specific primers used for RT-PCR assays were 5 -ATGAGTG- GTGGTTGCAGGC-39 and 59-TGACCTTTCAAATGCAGTAGATTCA-39 Female C57BL/6 mice (5–6 wk) were obtained from Joint Ventures Sipper for IFN-b and 59-TGTTACCAACTGGGACGACA-39 and 59-CTGGGT- BK Experimental Animal (Shanghai, China). All animal experiments were CATCTTTTCACGGT-39 for b-actin. Data are normalized to b-actin ex- undertaken in accordance
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