UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer

Abstract

The UBXD family is a diverse group of UBX (ubiquitin-regulatory X) domain-containing proteins in mammalian cells. Members of this family contain a UBX domain typically located at the carboxyl-terminal of the protein. In contrast to the UBX domain shared by all members of UBXD family, the amino-terminal domains are diverse and appear to carry out different roles in a subcellular localization-dependent manner. UBXD proteins are principally associated with the endoplasmic reticulum (ER), where they positively or negatively regulate the ER-associated degradation machinery (ERAD). The distinct protein interaction networks of UBXD proteins allow them to have specific functions independent of the ERAD pathway in a cell type- and tissue context-dependent manner. Recent reports have illustrated that a number of mammalian members of the UBXD family play critical roles in several proliferation and apoptosis pathways dysregulated in selected types of cancer. This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth.

UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells

“…The presence of the ubiquitin-regulatory X (UBX) domain, particularly in combination with the ubiquitin-associated (UBA) domain, allows selective members of the UBXD family to mediate ubiquitination and proteasomal degradation of diverse substrates as part of the ER-associated degradation (ERAD) mechanism or independent of ERAD (Lee et al, 2013;Park et al, 2016;Rezvani, 2016;Song et al, 2005). For our next step, we decided to determine whether UBXN2A can facilitate/enhance CHIP-dependent ubiquitination of mot-2.…”

“…Our previous findings showed that a UBX (ubiquitin‐regulatory X) domain‐containing protein (Rezvani, ) called UBXN2A binds and inhibits mot‐2, resulting in the induction of apoptosis and reduction in cell proliferation in both in vitro and in vivo models (Abdullah et al ., ; Sane et al ., ). UBXN2A binds to the substrate‐binding domain of mot‐2 and interferes with mot‐2's protein interaction networks (Sane et al ., ).…”

Domain Organization of the UBX Domain Containing Protein 9 and Analysis of Its Interactions With the Homohexameric AAA + ATPase p97 (Valosin-Containing Protein)

“…The largest family of regulatory cofactors is the Ubiquitin Regulatory X (UBX) domain containing protein family, which has thirteen members in human and eleven in D. discoideum ( Alexandru et al, 2008 ; Rijal et al, 2016 ). All members possess the eponymous, highly conserved UBX domain in their C-terminal region, which adopts a ubiquitin-like fold and is critical for the interaction with the N domain of p97 ( Rezvani, 2016 ). Five of the D. discoideum UBXD family members, among them UBX domain containing protein 9 (UBXD9), are orthologs of human UBXD proteins ( Rijal et al, 2016 ).…”

The AAA + ATPase valosin-containing protein (VCP)/p97/Cdc48 interaction network in Leishmania

“…Proteins such as UBXD1 to UBXD6, UBXD9 and UBXD11 contain only a UBX domain. The UBA (ubiquitin associated)-UBX cofactors, such as UBXD7, UBXD8 (FAF2), UBXD10 (p47), UBXD12 (FAF1) and UBXD13 also accommodate an UBA domain that is fundamental for interacting with ubiquitinated substrates 16 , 33 . Cofactors such as p47 harbor, in addition to the UBX and UBA domains important for their function in the UPS, a SHP (BS1, binding segment 1) motif as another site for interaction with the Nc subdomain of VCP 31 , 32 .…”