UBL4A

UBL4A Full Name

ubiquitin-like 4A

UBL4A Introduction

UBL4A, also known as GET4 or GdX, is a ~38 kDa ubiquitin-like protein that does not function as a canonical conjugating moiety but instead serves as a stable structural subunit of the BAG6 (Bat-3/Scythe) complex, together with BAG6 and TRC35. In the cytosol, this complex captures tail-anchored (TA) proteins—polypeptides defined by a single C-terminal transmembrane segment—and delivers them to the ER membrane–insertion machinery, preventing their mislocalization. The same complex also operates in endoplasmic reticulum–associated degradation (ERAD), where it acts as a ubiquitin ligase-associated holdase that keeps retrotranslocated, aggregation-prone polypeptides bearing exposed hydrophobic motifs in a soluble state as they travel toward the proteasome. Depletion of Ubl4A causes ERAD substrates to accumulate in detergent-insoluble aggregates, underscoring its role in protein-quality control. Structural and biochemical studies show that SGTA recognizes a noncanonical ubiquitin-like domain within the complex, coupling this chaperone activity to productive degradation.

Figure 1. SGTA binds Ubl4A UBL by a means that is distinct from the canonical mode of UBL recognition. (Source: Xu Y, et al. 2012)

Beyond cytosolic quality control, UBL4A participates in stress responses through relocalization of its complex. Under DNA damage, the normally cytoplasmic BAG6–UBL4A–GET4 assembly translocates to the nucleus, where it is required for proper recruitment of DNA-damage response factors to lesion sites and for cellular survival. The complex also regulates its own compartmentalization: TRC35/GET4 retains BAG6 in the cytoplasm, and a dedicated structural interface on BAG6 that is occupied by TRC35 controls its nucleo-cytoplasmic shuttling. Because the complex integrates membrane insertion, substrate solubility, and stress signaling, its subunits have been examined as modifiers in disease contexts ranging from cancer to neurodegeneration. These findings position UBL4A as a multifunctional scaffold rather than a simple modifier, illustrating how a single ubiquitin-like fold can be repurposed as an adapter that coordinates ER proteostasis with genome-stability pathways.

Alternate Names for UBL4A

UBL4A; ubiquitin-like 4A; ubiquitin like 4; UBL4; ubiquitin-like protein 4A; DXS254E; GDX; GET5; MDY2; TMA24; ubiquitin-like 4; ubiquitin-like protein GDX; G6PD; UBL4; DX254E;

• 1. Xu Y, et al. SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6-Ubl4A-Trc35 complex to promote endoplasmic reticulum-associated degradation. Cell Rep. 2012 Dec 27;2(6):1633-44.
  2. Krenciute G, et al. Nuclear BAG6-UBL4A-GET4 complex mediates DNA damage signaling and cell death. J Biol Chem. 2013 Jul 12;288(28):20547-57.