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Amphioxus TLR Signaling Adaptors Act As Negative Regulators In Novel Toll/IL-1 Receptor Homologous Region Adaptors Act as Negative Regulators in Amphioxus TLR Signaling This information is current as Jian Peng, Xin Tao, Rui Li, Jingru Hu, Jie Ruan, Ruihua of September 29, 2021. Wang, Manyi Yang, Rirong Yang, Xiangru Dong, Shangwu Chen, Anlong Xu and Shaochun Yuan J Immunol published online 31 August 2015 http://www.jimmunol.org/content/early/2015/08/30/jimmun ol.1403003 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/08/30/jimmunol.140300 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 29, 2021 *average 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 August 31, 2015, doi:10.4049/jimmunol.1403003 The Journal of Immunology Novel Toll/IL-1 Receptor Homologous Region Adaptors Act as Negative Regulators in Amphioxus TLR Signaling Jian Peng,*,1 Xin Tao,* Rui Li,* Jingru Hu,* Jie Ruan,* Ruihua Wang,* Manyi Yang,* Rirong Yang,* Xiangru Dong,* Shangwu Chen,* Anlong Xu,*,† and Shaochun Yuan* Studies have shown that the basal chordate amphioxus possesses an extraordinarily complex TLR system, including 39 TLRs and at least 40 Toll/IL-1R homologous region (TIR) adaptors. Besides homologs to MyD88 and TIR domain-containing adaptor mol- ecule (TICAM), most amphioxus TIR adaptors exhibit domain architectures that are not observed in other species. To reveal how these novel TIR adaptors function in amphioxus Branchiostoma belcheri tsingtauense (bbt), four representatives, bbtTIRA, bbtTIRB, bbtTIRC, and bbtTIRD, were selected for functional analyses. We found bbtTIRA to show a unique inhibitory role in amphioxus TICAM-mediated pathway by interacting with bbtTICAM and bbt receptor interacting protein 1b, whereas Downloaded from bbtTIRC specifically inhibits the amphioxus MyD88-dependent pathway by interacting with bbtMyD88 and depressing the polyubiquitination of bbt TNFR-associated factor 6. Although both bbtTIRB and bbtTIRD are located on endosomes, the TIR domain of bbtTIRB can interact with bbtMyD88 in the cytosol, whereas the TIR domain of bbtTIRD is enclosed in endosome, suggesting that bbtTIRD may be a redundant gene in amphioxus. This study indicated that most expanded TIR adaptors play nonredundant regulatory roles in amphioxus TLR signaling, adding a new layer to understanding the diversity and complexity of innate immunity at basal chordate. The Journal of Immunology, 2015, 195: 000–000. http://www.jimmunol.org/ oll-like receptors (TLRs) are a class of proteins that induction of type I IFN. The MyD88-dependent pathway is uni- recognize structurally conserved molecules derived from versal for all TLRs except TLR3, whereas the TRIF-dependent T microbes collectively referred to as pathogen-associated pathway is specifically used by TLR3 and TLR4 (3). When re- molecular patterns (1, 2). In mammals, upon ligand stimulation, cruited by TLR4, MyD88 requires MyD88 adaptor-like (MAL, the MyD88-dependent and Toll/IL-1R homologous region (TIR) also known as TIRPA), whereas TRIF needs TRIF-related adaptor domain-containing adaptor inducing IFN-b (TRIF)–dependent molecule (TRAM) as a partner (2, 4). The fifth adaptor SARM pathways can be triggered, leading to activation of NF-kB and the plays an inhibitory role in the TRIF-dependent pathway (5, 6). by guest on September 29, 2021 As an important component of the innate immune system, mammalian TLR signaling is tightly regulated to avoid extreme *State Key Laboratory of Biocontrol, Guangdong Key Laboratory of Pharmaceutical Functional Genes, College of Life Sciences, Sun Yat-Sen University, Guangzhou immune responses and to maintain tissue homeostasis (7). At the 510275, People’s Republic of China; and †Beijing University of Chinese Medicine, receptor level, the TLR4 homolog, radioprotective 105-kDa pro- Beijing 100029, People’s Republic of China tein (RP105, also called CD180) inhibits LPS-TLR4 binding and 1 Current address: Department of Biotechnology, Guizhou Medical University, impairs LPS-mediated NF-kB activation. Suppression of tumori- Guiyang, Guizhou Province, People’s Republic of China. genicity 2–related protein also inhibits TLR4 signaling by com- Received for publication December 2, 2014. Accepted for publication August 3, 2015. peting for MyD88 binding (8, 9). Dominant-negative proteins This work was supported by National Basic Research Program (973) Project generated by stimulus-dependent alternative splicing are also 2013CB835303, National Natural Science Foundation of China Projects 31270018, regulators at the adaptor level. For example, an LPS-inducible 31470846, and 30730089, and New Star of Pearl River on Science and Technology splice variant of MyD88, MyD88s, is a dominant negative in- of Guangzhou Project 2014J2200017. hibitor of TLR/IL-1R–induced NF-kB activation (10). The splice The sequences presented in this article have been submitted to the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov/genbank) un- variant IL-1R–associated kinase (IRAK)-1c and IRAK-M are der accession numbers KM288437, KM288438, KM288439, and KM288440. dominant-negative IRAK forms that play negative regulatory roles Address correspondence and reprint requests to Dr. Anlong Xu and Dr. Shaochun in Toll/IL-1R–induced inflammatory signaling (11, 12). In addi- Yuan, State Key Laboratory of Biocontrol, Department of Biochemistry, College of tion, posttranslation modification is widely used in negative Life Sciences, Sun Yat-Sen University, 135 Xingangxi Road, Guangzhou 510275, People’s Republic of China. E-mail addresses: [email protected] (A.X.) and feedback regulation of TLR signal (13, 14). For instance, activa- [email protected] (S.Y.) tion of the MyD88-dependent pathway leads to K63-linked The online version of this article contains supplemental material. polyubiquitination of TNFR-associated factor 6 (TRAF6) and Abbreviations used in this article: ABIN-1, A20 binding and inhibitor of NF-kB; the subsequent activation of the inhibitor of NF-kB kinase (IKK) ABL2, abelson murine leukemia viral oncogene homolog 2; bbt, Branchiostoma complex (15), whereas the K48-linked polyubiquitination of belcheri tsingtauense; bbtRIP1b, bbt receptor interacting protein 1b; CARD, caspase recruitment domain; Co-IP, coimmunoprecipitation; ER, endoplasmic reticulum; TRAF6 results in proteasomal degradation of TRAF6 and inhi- EST, expressed sequence tag; FPP, fluorescence protease protection; HEK, human bition of NF-kB (16). Because ubiquitination is a reversible pro- embryonic kidney; IKK, inhibitor of NF-kB kinase; IRAK, IL-1R–associated kinase; LTA, lipoteichoic acid; MyD88s, splice variant of MyD88; TICAM, TIR domain- cess, deubiquitination of TRAF6 is another effective feedback containing adaptor molecule; TIR, Toll/IL-1R homologous region; TRAF6, regulation of TLR signaling. TNFR-associated factor 6; TRAM, TRIF-related adaptor molecule; TRIF, TIR Compared with vertebrates, basal deuterostomes possess greatly domain-containing adaptor inducing IFN-b. expanded TLR repertoires. For example, the echinoderm sea urchin Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 has 222 TLRs and up to 26 potential TIR adaptors, whereas the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403003 2 TIR ADAPTORS NEGATIVELY REGULATE TLR PATHWAY IN AMPHIOXUS cephalochordate amphioxus possesses at least 39 TLRs and .40 For the NF-kB–specific inhibitor helenalin-treated experiments, the TIR adaptors (17). Among these adaptors, amphioxus MyD88, adult amphioxus were separated into three groups and treated with: 1) TRAM-like [also known as amphioxus TIR domain-containing DMSO as a negative control, 2) the LPS and LTA (1 mg/ml) mixtures, or 3) helenalin administered before inoculation with the LPS and LTA mix- adaptor molecule (TICAM)], and SARM have been well studied. tures (15 ml per animal). The animals were cultured in separate tanks, and Amphioxus MyD88 was shown to mediate the activation of NF- the intestines from five individuals were collected at 3 h postinjection as kB through its middle and death domains, whereas TICAM was a single sample. shown to mediate the most primitive TRIF-dependent activation The following primer pairs were used: BbtTIRA-F: 59-GGCTATCA- GGCTCTACGGACTTC-39, BbtTIRA-R: 59-CGCTTGACTTGCTGTTGC- of NF-kB (18–20). Amphioxus SARM plays inhibitory roles in TTGT-39; BbtTIRB-F: 59-TGGTCTACTTCGGTGGCTTGGA-39, BbtTIRB-R: both MyD88- and TICAM-dependent pathways by interacting 59-CGGCTCATCGCTCTGTTCATCTTG-39;BbtTIRC-F:59-GTCATC- with MyD88, TRAF6, and TICAM (19, 21). Recently, ubiquitination GGTGTCCAAGTT-39,BbtTIRC-R:59-TCTCCTCCAGCATGTCAT-39; was shown to be essential in regulating the activation of amphi- BbtTIRD-F: 59-AGCCTTCTACTGGACATACCTGAG-39,BbtTIRD-R:59-CA-
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