# TICAM1

## Overview
TICAM1, also known as TIR domain-containing adaptor molecule 1, is a gene that encodes a critical adaptor protein involved in the Toll-like receptor (TLR) signaling pathway. The protein, commonly referred to as TRIF, plays a pivotal role in the MyD88-independent pathway, particularly in the immune response to viral infections. As an adaptor protein, TRIF is integral to the activation of transcription factors such as NF-κB and IRF3, which are essential for the production of type I interferons and pro-inflammatory cytokines (Akira2004Toll-like; Fitzgerald2003LPSTLR4). Structurally, TRIF contains several domains, including a TIR domain and a receptor-interacting protein homotypic interaction motif (RHIM), which facilitate its interactions with other proteins in the signaling cascade (Enokizono2013Structures; Ullah2013The). These interactions are crucial for modulating immune responses and maintaining immune homeostasis, highlighting the gene's significance in both innate immunity and inflammatory regulation (Luo2019Signalling; Miyashita2021TICAM1TRIF).

## Structure
The TICAM1 protein, also known as TRIF, is a crucial adaptor in the Toll-like receptor (TLR) signaling pathway. Its molecular structure includes several distinct domains. The N-terminal domain (NTD) of TICAM1 is composed of eight alpha-helices, forming a structure similar to the interferon-induced protein with tetratricopeptide repeats (IFIT) family. This domain is involved in self-regulation by interacting with the TIR domain, suppressing TRIF-mediated activation of signaling pathways (Ullah2013The).

The TIR domain of TICAM1 is essential for protein-protein interactions, particularly in interferon signaling. It consists of five parallel β-strands surrounded by six or seven α-helices, forming a core structure. This domain facilitates interactions with TLR3 and TRAM, and its oligomerization is critical for downstream signaling (Enokizono2013Structures).

TICAM1 also contains a receptor-interacting protein homotypic interaction motif (RHIM) in the C-terminal region, which enables associations with RIP1 and RIP3, leading to NF-κB activation and cell death (Ullah2013The). The protein's structure is further characterized by specific interaction sites, such as the RK and QI sites, which are crucial for binding with TICAM2 (Enokizono2013Structures).

## Function
TICAM1, also known as TRIF, is a crucial adaptor protein in the Toll-like receptor (TLR) signaling pathway, particularly involved in the MyD88-independent pathway. It plays a significant role in the immune response by mediating downstream signaling of TLR3 and TLR4, which are responsible for recognizing viral components like double-stranded RNA (Akira2004Toll-like; Miyashita2021TICAM1TRIF). In healthy human cells, TICAM1 is essential for the activation of transcription factors such as NF-κB and IRF3, leading to the production of type I interferons (IFN-β) and pro-inflammatory cytokines, which are crucial for antiviral defense and inflammation regulation (Akira2004Toll-like; Fitzgerald2003LPSTLR4).

TICAM1 is primarily active in the cytoplasm and endosomes of immune cells, where it interacts with other adaptor proteins like TRAM to facilitate TLR4-mediated signaling (Luo2019Signalling). It also plays a role in modulating IL-17 receptor-mediated inflammatory responses by interacting with the adaptor protein Act1, thereby inhibiting excessive inflammatory signaling and maintaining immune homeostasis (Miyashita2021TICAM1TRIF). This regulatory function is crucial in preventing excessive inflammation and autoimmune reactions (Miyashita2021TICAM1TRIF).

## Clinical Significance
Mutations and alterations in the TICAM1 gene have been associated with various diseases and conditions. In the context of autoimmune and inflammatory diseases, TICAM1 plays a crucial role in modulating IL-17A-mediated immune responses. Deficiency in TICAM1 can lead to enhanced inflammatory responses, as seen in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, where TICAM1 knockout mice exhibited exacerbated symptoms due to increased immune cell infiltration in the central nervous system (Miyashita2021TICAM1TRIF).

TICAM1 is also implicated in thyroid cancer risk. Single-nucleotide polymorphisms (SNPs) in the TICAM1 gene have been significantly associated with increased risk of papillary and follicular thyroid cancers in a German population, suggesting that genetic variations in TICAM1 may contribute to cancer susceptibility (Sigurdson2016Selected).

In the context of viral infections, down-regulation of TICAM1 has been observed during rhinovirus infections, which impairs the host's antiviral response by reducing interferon production. This down-regulation is linked to increased viral replication, highlighting TICAM1's role in antiviral defense (Tao2012Negative). Additionally, polymorphisms in TICAM1 have been associated with susceptibility to community-acquired pneumonia in children, indicating its role in respiratory infections (Yang2020Correlation).

## Interactions
TICAM1, also known as TRIF, is a key adaptor protein involved in the Toll-like receptor (TLR) signaling pathways, particularly TLR3 and TLR4. It interacts with several proteins to mediate immune responses. TICAM1 directly binds to TRAF2 and TRAF6, which are crucial for the activation of the interferon (IFN)-β promoter and the transcription factors NF-κB and IRF-3. These interactions occur at the N-terminal region of TICAM1 and facilitate its polyubiquitination, a process essential for sustaining TICAM1 signaling (Sasai2010Direct).

TICAM1 also interacts with TRAF3, which is involved in TLR3-mediated type-I IFN signaling. This interaction remains intact even when TRAF2 and TRAF6 binding sites are mutated, suggesting the presence of other binding sites (Sasai2010Direct). The protein 14-3-3-zeta is another binding partner of TICAM1, essential for TLR3-mediated IFN-β promoter activation and NF-κB activation. This interaction is dependent on the phosphorylation of TICAM1, facilitated by TBK1 (Funami20161433zeta).

TICAM1 also associates with Act1, a key adaptor in the IL-17 signaling pathway, and suppresses IL-17 receptor-mediated inflammatory responses by inhibiting the interaction between Act1 and IL-17RA (Miyashita2021TICAM1TRIF). These interactions highlight TICAM1's role in modulating immune and inflammatory responses.


## References


[1. (Yang2020Correlation) Yong Yang, Suiyu Yang, Zongbo Chen, and Li Liu. Correlation betweenticam1gene polymorphisms and community‐acquired pneumonia in children. Journal of Biochemical and Molecular Toxicology, April 2020. URL: http://dx.doi.org/10.1002/jbt.22503, doi:10.1002/jbt.22503. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jbt.22503)

[2. (Tao2012Negative) Shasha Tao, Lingxiang Zhu, Pakkei Lee, Wai-ming Lee, Kenneth Knox, Jie Chen, Yuanpu Peter Di, and Yin Chen. Negative control of tlr3 signaling by ticam1 down-regulation. American Journal of Respiratory Cell and Molecular Biology, 46(5):660–667, May 2012. URL: http://dx.doi.org/10.1165/rcmb.2011-0340OC, doi:10.1165/rcmb.2011-0340oc. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1165/rcmb.2011-0340OC)

[3. (Sigurdson2016Selected) Alice J. Sigurdson, Alina V. Brenner, James A. Roach, Lilia Goudeva, Jörg A. Müller, Kai Nerlich, Christoph Reiners, Robert Schwab, Liliane Pfeiffer, Melanie Waldenberger, Melissa Braganza, Li Xu, Erich M. Sturgis, Meredith Yeager, Stephen J. Chanock, Ruth M. Pfeiffer, Michael Abend, and Matthias Port. Selected single-nucleotide polymorphisms infoxe1,serpina5,fto,evpl,ticam1andscarb1are associated with papillary and follicular thyroid cancer risk: replication study in a german population. Carcinogenesis, 37(7):677–684, April 2016. URL: http://dx.doi.org/10.1093/carcin/bgw047, doi:10.1093/carcin/bgw047. This article has 32 citations and is from a peer-reviewed journal.](https://doi.org/10.1093/carcin/bgw047)

[4. (Ullah2013The) M. Obayed Ullah, Thomas Ve, Matthew Mangan, Mohammed Alaidarous, Matthew J. Sweet, Ashley Mansell, and Bostjan Kobe. The tlr signalling adaptor trif/ticam-1 has an n-terminal helical domain with structural similarity to ifit proteins. Acta Crystallographica Section D Biological Crystallography, 69(12):2420–2430, November 2013. URL: http://dx.doi.org/10.1107/s0907444913022385, doi:10.1107/s0907444913022385. This article has 13 citations.](https://doi.org/10.1107/s0907444913022385)

[5. (Funami20161433zeta) Kenji Funami, Misako Matsumoto, Chikashi Obuse, and Tsukasa Seya. 14-3-3-zeta participates in tlr3-mediated ticam-1 signal-platform formation. Molecular Immunology, 73:60–68, May 2016. URL: http://dx.doi.org/10.1016/j.molimm.2016.03.010, doi:10.1016/j.molimm.2016.03.010. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.molimm.2016.03.010)

[6. (Akira2004Toll-like) Shizuo Akira and Kiyoshi Takeda. Toll-like receptor signalling. Nature Reviews Immunology, 4(7):499–511, July 2004. URL: http://dx.doi.org/10.1038/nri1391, doi:10.1038/nri1391. This article has 6479 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nri1391)

[7. (Enokizono2013Structures) Yoshiaki Enokizono, Hiroyuki Kumeta, Kenji Funami, Masataka Horiuchi, Joy Sarmiento, Kazuo Yamashita, Daron M. Standley, Misako Matsumoto, Tsukasa Seya, and Fuyuhiko Inagaki. Structures and interface mapping of the tir domain-containing adaptor molecules involved in interferon signaling. Proceedings of the National Academy of Sciences, 110(49):19908–19913, November 2013. URL: http://dx.doi.org/10.1073/pnas.1222811110, doi:10.1073/pnas.1222811110. This article has 58 citations.](https://doi.org/10.1073/pnas.1222811110)

[8. (Fitzgerald2003LPSTLR4) Katherine A. Fitzgerald, Daniel C. Rowe, Betsy J. Barnes, Daniel R. Caffrey, Alberto Visintin, Eicke Latz, Brian Monks, Paula M. Pitha, and Douglas T. Golenbock. Lps-tlr4 signaling to irf-3/7 and nf-κb involves the toll adapters tram and trif. The Journal of Experimental Medicine, 198(7):1043–1055, September 2003. URL: http://dx.doi.org/10.1084/jem.20031023, doi:10.1084/jem.20031023. This article has 944 citations.](https://doi.org/10.1084/jem.20031023)

[9. (Luo2019Signalling) Lin Luo, Richard M. Lucas, Liping Liu, and Jennifer L. Stow. Signalling, sorting and scaffolding adaptors for toll-like receptors. Journal of Cell Science, December 2019. URL: http://dx.doi.org/10.1242/jcs.239194, doi:10.1242/jcs.239194. This article has 61 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.239194)

[10. (Miyashita2021TICAM1TRIF) Yusuke Miyashita, Takahisa Kouwaki, Hirotake Tsukamoto, Masaaki Okamoto, Kimitoshi Nakamura, and Hiroyuki Oshiumi. Ticam-1/trif associates with act1 and suppresses il-17 receptor–mediated inflammatory responses. Life Science Alliance, 5(2):e202101181, November 2021. URL: http://dx.doi.org/10.26508/lsa.202101181, doi:10.26508/lsa.202101181. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.26508/lsa.202101181)

[11. (Sasai2010Direct) Miwa Sasai, Megumi Tatematsu, Hiroyuki Oshiumi, Kenji Funami, Misako Matsumoto, Shigetsugu Hatakeyama, and Tsukasa Seya. Direct binding of traf2 and traf6 to ticam-1/trif adaptor participates in activation of the toll-like receptor 3/4 pathway. Molecular Immunology, 47(6):1283–1291, March 2010. URL: http://dx.doi.org/10.1016/j.molimm.2009.12.002, doi:10.1016/j.molimm.2009.12.002. This article has 72 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.molimm.2009.12.002)