UBQLN4
Function
Regulator of protein degradation that mediates the proteasomal targeting of misfolded, mislocalized or accumulated proteins (PubMed:15280365, PubMed:27113755, PubMed:29666234, PubMed:30612738). Acts by binding polyubiquitin chains of target proteins via its UBA domain and by interacting with subunits of the proteasome via its ubiquitin-like domain (PubMed:15280365, PubMed:27113755, PubMed:30612738). Key regulator of DNA repair that represses homologous recombination repair: in response to DNA damage, recruited to sites of DNA damage following phosphorylation by ATM and acts by binding and removing ubiquitinated MRE11 from damaged chromatin, leading to MRE11 degradation by the proteasome (PubMed:30612738). MRE11 degradation prevents homologous recombination repair, redirecting double-strand break repair toward non-homologous end joining (NHEJ) (PubMed:30612738). Specifically recognizes and binds mislocalized transmembrane-containing proteins and targets them to proteasomal degradation (PubMed:27113755). Collaborates with DESI1/POST in the export of ubiquitinated proteins from the nucleus to the cytoplasm (PubMed:29666234). Also plays a role in the regulation of the proteasomal degradation of non-ubiquitinated GJA1 (By similarity). Acts as an adapter protein that recruits UBQLN1 to the autophagy machinery (PubMed:23459205). Mediates the association of UBQLN1 with autophagosomes and the autophagy-related protein LC3 (MAP1LC3A/B/C) and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion (PubMed:23459205).
Involvement in disease
Amyotrophic lateral sclerosis
ALS
A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.
None
Disease susceptibility is associated with variants affecting the gene represented in this entry.
Defects in UBQLN4 are the cause of the UBQLN4 deficiency syndrome (UBDS) (PubMed:30612738). Patients display intellectual impairment, growth retardation, microcephaly, facial dysmorphism, hearing loss, ataxia and anemia (PubMed:30612738). Cells display genomic instability characterized by hypersensitivity to genotoxic agents, leading to enhanced apoptotic cell death in response to DNA damage (PubMed:30612738).
Post-translational modifications
Phosphorylated by ATM at Ser-318 in response to DNA damage, leading to localization in the nucleus and recruitment to sites of DNA damage.
Ubiquitinated; this does not lead to proteasomal degradation (PubMed:15280365). May undergo both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:15280365).
Tissue Specificity
Highly expressed in pancreas, kidney, skeletal muscle, heart and throughout the brain, and at lower levels in placenta, lung and liver.
Cellular localization
- Nucleus
- Cytoplasm
- Chromosome
- Endoplasmic reticulum
- Cytoplasm
- Perinuclear region
- Cytoplasmic vesicle
- Autophagosome
- Colocalizes with the proteasome, both in nucleus and cytoplasm (PubMed:15280365). Exported from the nucleus following interaction with DESI1/POST (PubMed:29666234). In response to DNA damage and phosphorylation at Ser-318 by ATM, localizes to the nucleus and is recruited to sites of DNA damage (PubMed:30612738).
Alternative names
C1orf6, CIP75, UBIN, UBQLN4, Ubiquilin-4, Ataxin-1 interacting ubiquitin-like protein, Ataxin-1 ubiquitin-like-interacting protein A1U, Connexin43-interacting protein of 75 kDa, A1Up