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

Oncotarget. 2014 Oct 30;5(20):10084-99. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Apoptosis / physiology
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • NF-kappa B / metabolism
  • NF-kappaB-Inducing Kinase
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Transfection
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • HAX1 protein, human
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • Protein Serine-Threonine Kinases