HAX-1: A multifunctional protein with emerging roles in human disease

Abstract

HS-1-associated protein X-1 (HAX-1) was identified more than 10 years ago as a novel protein with ubiquitous tissue expression and a predominantly mitochondrial localization at the subcellular level. Recent studies have shown that homozygous mutations in the HAX1 gene are associated with autosomal recessive forms of severe congenital neutropenia (also known as Kostmann disease), and results from studies in mice and men are beginning to unravel a prominent role for HAX-1 in apoptosis signaling not only in the hematopoietic compartment, but also in the central nervous system. Moreover, several different cellular and viral binding partners of HAX-1 have been identified thus pointing toward a complex and multifunctional role of this protein. HAX-1 has also been shown to bind to the 3′ untranslated regions of certain mRNAs and could therefore contribute to the regulation of transport and/or stability of such transcripts. The present review discusses the emerging and divergent roles of HAX-1, including its involvement in cell migration, apoptosis signaling, and mRNA surveillance. The importance of HAX-1 in human disease is also highlighted and outstanding questions that remain to be addressed are identified.

Introduction

HS-1-associated protein X-1 (HAX-1) was originally identified as a 35 kDa protein that interacts with HS-1, a Src kinase substrate, and was suggested to be involved in B cell signal transduction [1]. Subsequently, HAX-1 has been shown to interact with a number of cellular and viral proteins, thus testifying to its involvement in multiple signaling pathways and cellular processes. HAX-1 is ubiquitously expressed in murine and human tissues [2], [3] and appears to be predominantly localized to mitochondria, and to a lesser extent to the endoplasmic reticulum and nuclear membrane [1]. Moreover, based on its apparent homology with the anti-apoptotic protein, B cell lymphoma/leukemia-2 (Bcl-2), HAX-1 was suggested to be involved in the regulation of apoptosis or programmed cell death [1]. Several in vitro studies support this notion, and a recent in vivo study showed that the homozygous deletion of HAX1 in mice results in excessive apoptosis of neurons and postnatal lethality caused by loss of motor coordination and function, leading to failure to eat or drink [4].

Importantly, homozygous mutations were revealed in the HAX1 gene in patients with autosomal recessive forms of severe congenital neutropenia (SCN) or Kostmann disease, a condition characterized by a maturation arrest in the bone marrow and a lack of mature neutrophils in peripheral blood [5]. These findings demonstrate that HAX-1 is a major regulator of myeloid cell homeostasis in humans. Recent studies have also suggested that HAX-1 may play a role in the regulation of calcium homeostasis and cell survival in cardiac tissue [6]. In addition, HAX-1 was found to be overexpressed in the skin of patients with psoriasis, a chronic inflammatory disease characterized by increased proliferation of the epidermis and resistance to apoptosis [7]. There is also emerging evidence that HAX-1 is highly expressed or overexpressed in various types of human malignancies [7], [8].

Taken together, an increasing number of studies in recent years have suggested that HAX-1 is a multifunctional protein. Here, we provide an overview of our current understanding of the regulation and expression of the HAX1 gene and the corresponding HAX-1 protein, and a discussion of the various HAX-1-interacting partners identified to date, along with an exploration of the roles attributed to HAX-1 in cellular processes and in the pathogenesis of human disease.