UBQLN2

UBQLN2 Full Name

ubiquilin 2

UBQLN2 Introduction

UBQLN2, also called PLIC2, is a ~62 kDa protein containing an N-terminal ubiquitin-like (UBL) domain and a C-terminal ubiquitin-associated (UBA) domain. These two domains allow ubiquilin 2 to bind simultaneously to ubiquitin ligases and to the proteasome, functioning as an adaptor that delivers ubiquitinated substrates to the degradation machinery. The UBL domain can engage the proteasome, while the UBA domain captures ubiquitin chains, and ubiquilin 2 can also associate with Hsp70-family chaperones, placing it at the crossroads of degradation and protein-folding networks. UBQLN2 is best known for its role in neurodegeneration: dominant missense mutations in the gene cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), establishing UBQLN2 as a causal gene for these disorders. The disease-linked mutations cluster in and around the PXX domain of the UBA domain, and subsequent patient screening has identified additional pathogenic variants outside this region, including cases presenting as pure FTD without motor neuron involvement.

Figure 1. The location and genetic conservation of the mutations in UBQLN2 gene. (Source: Huang X, et al. 2017)

At the cellular level, mutant UBQLN2 disrupts protein-quality control. ALS-associated variants drive accumulation of polyubiquitinated substrates and promote inclusion formation, sequestering both proteasomal and autophagic branches of degradation and impairing clearance of disease-associated proteins such as TDP-43. The mutant protein also perturbs stress-granule dynamics, linking its dysfunction to altered RNA-binding protein homeostasis. Transgenic mouse models expressing mutant UBQLN2 develop dendritic spine abnormalities and neuronal pathology that recapitulate features of human ALS/FTD, connecting the biochemical defects to structural and functional neuronal changes. The accumulation of ubiquilin-2–positive inclusions is a neuropathological hallmark shared across familial and sporadic ALS, extending the relevance of UBQLN2 biology beyond inherited cases. Together, these studies define UBQLN2 as a hub that couples ubiquitination to both proteasomal and autophagic turnover; when this coupling fails, misfolded proteins accumulate and contribute to selective vulnerability of motor neurons and cortical neurons.

Alternate Names for UBQLN2

UBQLN2; ubiquilin 2; DSK2; ALS15; CHAP1; N4BP4; PLIC2; HRIHFB2157; ubiquilin-2; Nedd4 binding protein 4; ubiquitin-like product Chap1/Dsk2; protein linking IAP with cytoskeleton 2;

• 1. Huang X, et al. No Evidence for Pathogenic Role of UBQLN2 Mutations in Sporadic Amyotrophic Lateral Sclerosis in the Mainland Chinese Population. PLoS One. 2017 Jan 26;12(1):e0170943.
  2. Deng HX, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Aug 21;477(7363):211-5.