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). Homooligomer (PubMed:15280365, PubMed:30612738). Binds signal sequences of proteins that are targeted to the endoplasmic reticulum (By similarity). Interacts (via UBA domain) with GJA1 (not ubiquitinated) and with ubiquitin; both compete for the same binding site (By similarity). Interacts (via UBA domain) with ubiquitin and with polyubiquitin chains (By similarity). Interacts (via ubiquitin-like domain) with PSMD2 and PSMD4, regulatory subunits of the 26S proteasome (PubMed:15280365). Interacts with ATXN1/SCA1; interaction with ATXN1 inhibits polyubiquitination of UBQLN4 and interferes with PSMD4 binding (PubMed:11001934, PubMed:15280365). Interacts with HERPUD1 (PubMed:18307982). Interacts (via ubiquitin-like domain) with UBQLN1 (via UBA domain) (PubMed:23459205). Interacts with UBQLN2 (PubMed:23459205). Interacts (via STI1 1 and 2 domains) with MAP1LC3A/B/C (PubMed:23459205). Interacts with BAG6 (PubMed:27113755). Interacts with MRE11 (when ubiquitinated); interaction with ubiquitinated MRE11 leads to MRE11 removal from chromatin (PubMed:30612738). Interacts with DESI1/POST; leading to nuclear export (PubMed:29666234). Interacts with BCL2A1 and BCL2L10 (PubMed:34245648). (Microbial infection) Interacts with Mumps virus protein SH. 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). Highly expressed in pancreas, kidney, skeletal muscle, heart and throughout the brain, and at lower levels in placenta, lung and liver. Up-regulated in aggressive tumors: expression is significantly increased in stage 3 and 4 neuroblastomas, compared to stage 1 disease. 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). 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). May be a potential prognostic marker in cancer patients. Extended N-terminus. Truncated N-terminus.