title: HAX1 regulates E3 ubiquitin ligase activity of cIAPs by promoting their dimerization.
abstract: HS-1-associated protein X-1 (HAX1) is a multi-functional protein which was first identified as a Hematopoietic cell specific Lyn Substrate 1 (HS1)-binding protein. Although the roles of HAX1 in apoptosis have been unraveled and HAX1 has been proposed to be involved in several diseases, additional roles of HAX1 are still being identified. Here, we demonstrated that HAX1 directly interacted with cellular Inhibitor of Apoptosis Proteins (cIAPs), ubiquitin E3 ligases which regulate the abundance of cellular proteins, via ubiquitin-dependent proteasomal degradation. We showed that HAX1 promotes auto-ubiquitination and degradation of cIAPs by facilitating the intermolecular homodimerization of RING finger domain. Moreover, HAX1 regulates the non-canonical Nuclear Factor-κB (NF-κB) signaling pathway by modulating the stability of NF-κB-Inducing Kinase (NIK), which is one of the substrates of cIAPs. Taken together, these results unveil a novel role of HAX1 in the non-canonical NF-κB pathway, and provide an important clue that HAX1 is a potential therapeutic target for the treatment of cancer.
authors.affiliation: Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea. College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Park
authors.affiliation: Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Chi
authors.affiliation: Cell Function Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Bae
authors.affiliation: Targeted Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea. Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Sunhong
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Sayeon
authors.initials: S
authors.lastname: Cho
authors.affiliation: Asan Institute for Life Sciences and Asan Medical Center, Seoul, Republic of Korea. Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Woo-Chan
authors.initials: WC
authors.lastname: Son
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Pyung Keun
authors.initials: PK
authors.lastname: Myung
authors.affiliation: Targeted Gene Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea. Department of Functional Genomics, Daejeon, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
authors.forename: Sung Goo
authors.initials: SG
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D000097782:NF-kappaB-Inducing Kinase; C104759:HAX1 protein, human; C494832:BIRC3 protein, human