TNF Receptor-associated Factor 6 (TRAF6) Plays Crucial Roles in Multiple Biological Systems Through Polyubiquitination-mediated NF-κB Activation

Overview

Journal Proc Jpn Acad Ser B Phys Biol Sci

Specialties Biology
Science

Date 2021 Apr 12

PMID 33840674

Citations 24

Authors

Mizuki Yamamoto

Jin Gohda

Taishin Akiyama

Jun-Ichiro Inoue

Affiliations

Soon will be listed here.

Abstract

NF-κB was first identified in 1986 as a B cell-specific transcription factor inducing immunoglobulin κ light chain expression. Subsequent studies revealed that NF-κB plays important roles in development, organogenesis, immunity, inflammation, and neurological functions by spatiotemporally regulating cell proliferation, differentiation, and apoptosis in several cell types. Furthermore, studies on the signal pathways that activate NF-κB led to the discovery of TRAF family proteins with E3 ubiquitin ligase activity, which function downstream of the receptor. This discovery led to the proposal of an entirely new signaling mechanism concept, wherein K63-ubiquitin chains act as a scaffold for the signaling complex to activate downstream kinases. This concept has revolutionized ubiquitin studies by revealing the importance of the nonproteolytic functions of ubiquitin not only in NF-κB signaling but also in a variety of other biological systems. TRAF6 is the most diverged among the TRAF family proteins, and our studies uncovered its notable physiological and pathological functions.

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References

Gohda J, Matsumura T, Inoue J . Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol. 2004; 173(5):2913-7. DOI: 10.4049/jimmunol.173.5.2913. View

Kobayashi N, Kadono Y, Naito A, Matsumoto K, Yamamoto T, Tanaka S . Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO J. 2001; 20(6):1271-80. PMC: 145527. DOI: 10.1093/emboj/20.6.1271. View

Ohtake F, Saeki Y, Ishido S, Kanno J, Tanaka K . The K48-K63 Branched Ubiquitin Chain Regulates NF-κB Signaling. Mol Cell. 2016; 64(2):251-266. DOI: 10.1016/j.molcel.2016.09.014. View

Taguchi Y, Gohda J, Koga T, Takayanagi H, Inoue J . A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals. Genes Cells. 2009; 14(11):1331-45. DOI: 10.1111/j.1365-2443.2009.01351.x. View

Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu Z . Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nat Immunol. 2003; 5(1):98-103. DOI: 10.1038/ni1014. View

Varney M, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N . Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med. 2015; 212(11):1967-85. PMC: 4612089. DOI: 10.1084/jem.20141898. View

Ye H, Arron J, Lamothe B, Cirilli M, Kobayashi T, Shevde N . Distinct molecular mechanism for initiating TRAF6 signalling. Nature. 2002; 418(6896):443-7. DOI: 10.1038/nature00888. View

Inman J, Robertson C, Mott J, Bissell M . Mammary gland development: cell fate specification, stem cells and the microenvironment. Development. 2015; 142(6):1028-42. DOI: 10.1242/dev.087643. View

Yamaguchi N, Ito T, Azuma S, Ito E, Honma R, Yanagisawa Y . Constitutive activation of nuclear factor-kappaB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines. Cancer Sci. 2009; 100(9):1668-74. PMC: 11158550. DOI: 10.1111/j.1349-7006.2009.01228.x. View

10.

Nakano H, Oshima H, Chung W, Ware C, Yagita H, Okumura K . TRAF5, an activator of NF-kappaB and putative signal transducer for the lymphotoxin-beta receptor. J Biol Chem. 1996; 271(25):14661-4. DOI: 10.1074/jbc.271.25.14661. View

11.

Inoue J, Ishida T, Tsukamoto N, Kobayashi N, Naito A, Azuma S . Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res. 2000; 254(1):14-24. DOI: 10.1006/excr.1999.4733. View

12.

Fata J, Kong Y, Li J, Sasaki T, Irie-Sasaki J, Moorehead R . The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000; 103(1):41-50. DOI: 10.1016/s0092-8674(00)00103-3. View

13.

Haljasorg U, Bichele R, Saare M, Guha M, Maslovskaja J, Kond K . A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. Eur J Immunol. 2015; 45(12):3246-56. DOI: 10.1002/eji.201545928. View

14.

Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J . Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40. Proc Natl Acad Sci U S A. 1999; 96(4):1234-9. PMC: 15446. DOI: 10.1073/pnas.96.4.1234. View

15.

Jones D, Nakashima T, Sanchez O, Kozieradzki I, Komarova S, Sarosi I . Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006; 440(7084):692-6. DOI: 10.1038/nature04524. View

16.

Ito-Kureha T, Koshikawa N, Yamamoto M, Semba K, Yamaguchi N, Yamamoto T . Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth. Cancer Res. 2014; 75(1):62-72. DOI: 10.1158/0008-5472.CAN-13-3455. View

17.

Dixit E, Kagan J . Intracellular pathogen detection by RIG-I-like receptors. Adv Immunol. 2013; 117:99-125. PMC: 3947775. DOI: 10.1016/B978-0-12-410524-9.00004-9. View

18.

Zhang D, Facchinetti V, Wang X, Huang Q, Qin J, Su B . Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways. EMBO J. 2005; 25(1):97-107. PMC: 1356356. DOI: 10.1038/sj.emboj.7600913. View

19.

Storci G, Sansone P, Mari S, DUva G, Tavolari S, Guarnieri T . TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol. 2010; 225(3):682-91. PMC: 2939957. DOI: 10.1002/jcp.22264. View

20.

Lomaga M, Yeh W, Sarosi I, Duncan G, Furlonger C, Ho A . TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 1999; 13(8):1015-24. PMC: 316636. DOI: 10.1101/gad.13.8.1015. View