Ubiquitin protein ligase E3 component n-recognin 4 (UBR4)

Ubiquitin protein ligase E3 component n-recognin 4 (UBR4) is a very large, multifunctional E3 and E4 ubiquitin ligase that plays a critical role in cellular protein quality control systems, including the N-end rule pathway and related degradation pathways[1][2][3][4][5]. UBR4 recognizes and ubiquitinates proteins with destabilizing N-terminal residues (N-degrons), facilitating their degradation primarily via the ubiquitin-proteasome system. It also works as an E4 ligase, amplifying ubiquitination signals by specifically extending lysine-48-linked ubiquitin chains on misfolded, aggregated, or otherwise unwanted proteins—frequently operating as part of multi-subunit complexes with cofactors such as KCMF1 and calmodulin[1][4]. UBR4 is involved in crucial stress-response pathways, including the clearance of oxidized proteins and regulation of stress-induced autophagy. It interacts with key cellular structures, functioning as both a cytoskeletal component in the cytoplasm and a chromatin scaffold in the nucleus[3][5]. UBR4 is essential for proteostasis in long-lived, metabolically active cells such as neurons and muscle cells; mutations or dysregulation of UBR4 have been linked to neurodegeneration, muscular atrophy, and cancer progression[2][3][4]. Its requirement in multiple protein quality control and cell surveillance mechanisms makes it a potential—but complicated—therapeutic target, as its inhibition could risk widespread proteostasis disruption. No drugs are currently known to directly modulate UBR4 in clinical use or trials[3][4].

Other names

UBR4KIAA0462KIAA1307p600RBAF600ZUBR1retinoblastoma-associated factor of 600 kDa600 kDa retinoblastoma protein-associated factorN-recognin-4E3 ubiquitin-protein ligase UBR4RING-type E3 ubiquitin transferase UBR4retinoblastoma-associated factor 600-like proteinzinc finger UBR1-type protein 1