Probable E3 ubiquitin-protein ligase HECTD2 (HECTD2)

HECTD2 is an E3 ubiquitin-protein ligase that contains a C-terminal HECT (Homologous to E6AP C-Terminus) domain responsible for transferring ubiquitin from an E2 conjugating enzyme to specific substrate proteins[3]. HECTD2 mediates polyubiquitination and subsequent proteasomal degradation of substrates such as PIAS1, a regulator of transcriptional activity and inflammation[1]. HECTD2-driven ubiquitination of PIAS1 enhances NF-κB signaling and proinflammatory responses, and nuclear entry of HECTD2 is required for this activity[1]. In cancer, particularly melanoma, HECTD2 expression is upregulated and drives cell proliferation, cell cycle progression, and promotes immune evasion by initiating several immunosuppressive pathways, including the COX2/prostaglandin E2 axis[2]. Elevated HECTD2 expression is associated with poor prognosis and reduced responsiveness to immune checkpoint inhibitors targeting PD-1 in melanoma[2]. HECTD2 interacts with a variety of immune-related genes and pathways, affecting both tumor cell-intrinsic proliferation and the tumor microenvironment[2]. Small molecule inhibitors (e.g., BC-1382) targeting the HECT domain of HECTD2 have shown in vitro inhibition, supporting potential therapeutic relevance[1].

Other names

Probable E3 ubiquitin-protein ligase HECTD2HECTD2FLJ37306HECT domain-containing protein 2HECT-type E3 ubiquitin transferase HECTD2HECT domain containing E3 ubiquitin protein ligase 2

Inhibition of HECT domain-dependent ubiquitin ligase activity, leading to stabilization of HECTD2 substrates such as PIAS1, suppression of downstream NF-κB activation, and/or modulation of cell proliferation and immune signaling pathways