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

Jin Sun Choi,Jeong-Hoon Kim,Sung Goo Park,Byoung Chul Park,Seung Wook Chi,Sunhong Kim,Sayeon Cho,Kwang-Hee Bae,Woo-Chan Son,Pyung Keun Myung

doi:10.18632/oncotarget.2459

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.

Highlights

HS-1-associated protein X-1(HAX1) is a ubiqui tously expressed, multifaceted protein with multiple protein-protein interaction domains [1]
Because X-linked inhibitor of apoptosis protein (XIAP) is a member of the Inhibitor of apoptosis (IAP) family proteins, we hypothesized that cellular Inhibitor of Apoptosis Proteins (cIAPs) would interact with the HAX1 protein
Using proximity ligation assay technique, we showed that endogenous HAX1 is localized in the vicinity of cIAP1 and cIAP2 (Supplementary Figure S2)

Summary

Introduction

HS-1-associated protein X-1(HAX1) is a ubiqui tously expressed, multifaceted protein with multiple protein-protein interaction domains [1]. Reminiscent to the roles of members of the Bcl-2 family, HAX1 prevents apoptosis by directly inhibiting the processing of www.impactjournals.com/oncotarget caspase 9 in cardiac myocytes [3] or by modulating Ca2+ homeostasis via interacting with phospholamban (PLN) and sarcoplasmic reticulum Ca2+ ATPase (SERCA2) [4, 5]. Another mechanism by which HAX1 prevents apoptosis is that HAX1 contributes to presenilin-associated, rhomboidlike-mediated processing and activation of the serine protease HtrA2, thereby preventing accumulation of proapoptotic Bax in the outer mitochondrial membrane [6]. Homozygous null mice for HAX1 recapitulate the phenotype of human neutropenia, leading to postnatal lethality [6]

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Conclusion