Ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2)

Ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) is a member of the RBR (RING-between-RING) E3 ubiquitin ligase family, distinguished by a unique domain architecture, including RING1, IBR, and RING2 domains, as well as the ARIH-specific UBAL and Ariadne domains[5][2][3]. ARIH2 acts as an enzyme that catalyzes the transfer of ubiquitin to target proteins—primarily through collaboration with the E2 conjugating enzyme UBE2L3—thereby regulating their stability and degradation[5][2]. The enzyme is regulated through an autoinhibitory Ariadne domain that masks its catalytic site, releasing inhibition when engaged in multiprotein complexes such as the Cullin-5/RBX2 ligase complex[2][3]. Biologically, ARIH2 plays central roles in ubiquitin-mediated proteolysis, control of the cell cycle (most notably via direct ubiquitination of the tumor suppressor p21), DNA damage response, modulation of inflammatory signaling (inhibiting NF-κB activity and promoting degradation of immune regulators including IκBβ and NLRP3), as well as skeletal muscle development[1][4]. ARIH2 is implicated in cancer (notably gastric cancer where its overexpression promotes cell proliferation and represses DNA damage response) and in inflammatory diseases (e.g., inflammatory bowel disease)[1][4]. Potential as a therapeutic target is supported by evidence of its involvement in pathways central to oncogenesis, immunity, and possibly tissue regeneration, though approved drugs targeting ARIH2 are not described in public literature.

Other names

ARIH2ARI2TRIAD1HT005ARI-2Protein ariadne-2 homologTriad1 proteinall-trans retinoic acid inducible RING fingerariadne homolog 2

Drugs targeting ARIH2 (hypothetically, as specific inhibitors are not listed in the literature) would likely inhibit its E3 ubiquitin ligase activity, modulating the degradation of its substrates such as p21 and NLRP3[4][1].