Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Degradação Associada com o Retículo Endoplasmático/fisiologia , Metabolismo Energético/fisiologia , Fatores de Crescimento de Fibroblastos/biossíntese , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Animais , HumanosRESUMO
Endoplasmic reticulum-associated degradation (ERAD) plays a crucial role in turnover of defective secretory proteins to maintain protein homeostasis. Cha et al. (2018) revealed that the anti-diabetic drug metformin induces ERAD of programmed death ligand (PD-L1), which attenuates tumor growth.
Assuntos
Degradação Associada com o Retículo Endoplasmático , Metformina , Animais , Antígeno B7-H1 , Retículo Endoplasmático , Proteínas/genéticaRESUMO
The mammalian ubiquitin ligase Hrd1 is the central component of a complex facilitating degradation of misfolded proteins during the ubiquitin-proteasome-dependent process of ER-associated degradation (ERAD). Hrd1 associates with cofactors to execute ERAD, but their roles and how they assemble with Hrd1 are not well understood. Here, we identify crucial cofactor interaction domains within Hrd1 and report a previously unrecognised evolutionarily conserved segment within the intrinsically disordered cytoplasmic domain of Hrd1 (termed the HAF-H domain), which engages complementary segments in the cofactors FAM8A1 and Herp (also known as HERPUD1). This domain is required by Hrd1 to interact with both FAM8A1 and Herp, as well as to assemble higher-order Hrd1 complexes. FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery.