HAX1 regulates E3 ubiquitin ligase activity of cIAPs by promoting their dimerization

// Jin Sun Choi 1 , 8 , Byoung Chul Park 1 , Seung Wook Chi 1 , Kwang-Hee Bae 2 , Sunhong Kim 3 , 10 , Sayeon Cho 5 , Woo-Chan Son 6 , 7 , Pyung Keun Myung 8 , Jeong-Hoon Kim 4 , 9 , Sung Goo Park 1 1 Medical Proteomics Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea 2 Cell Function Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea 3 Targeted Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea 4 Targeted Gene Regulation Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon, Republic of Korea 5 College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea 6 Asan Institute for Life Sciences and Asan Medical Center, Seoul, Republic of Korea 7 Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 8 College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea 9 Department of Functional Genomics, Daejeon, Republic of Korea 10 Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea Correspondence to: Dr. Sung Goo Park, e-mail: sgpark@kribb.re.kr Dr. Jeong-Hoon Kim, e-mail: jhoonkim@kribb.re.kr Received: June 16, 2014      Accepted: September 06, 2014      Published: September 29, 2014 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.