Hrd1

Hrd1 is an endoplasmic reticulum (ER)-resident E3 ubiquitin ligase that plays a central role in ER-associated degradation (ERAD), the quality-control pathway that removes misfolded proteins from the secretory system. In humans the enzyme is encoded by the SYVN1 gene and is sometimes referred to as synoviolin; in yeast and other organisms, the protein is known as Hrd1. It is a multi-pass membrane protein that features a cytosolic RING-type ubiquitin ligase domain responsible for catalyzing the transfer of ubiquitin to substrate proteins.

In ERAD, Hrd1 forms part of a larger protein complex that coordinates recognition, retrotranslocation, ubiquitination, and dislocation of misfolded substrates from the ER to the cytosol. The core complex interacts with other ERAD components such as Derlin family proteins and SEL1L, helping to bridge luminal or membrane substrates to the cytosolic ubiquitin–proteasome system. Once ubiquitinated, substrate proteins are extracted by the p97/VCP ATPase and directed to the proteasome for degradation, thereby maintaining proteostasis in the secretory pathway.

Expression of SYVN1 is widespread in human tissues, reflecting its essential role in protein quality control. Beyond housekeeping ERAD, HRD1 has been studied in disease contexts. In rheumatoid arthritis, HRD1 (synoviolin) is notably abundant in synovial tissue, and experimental work suggests it may promote survival of stressed synovial cells by sustaining ERAD, potentially influencing disease progression.

Genetic disruption or dysfunction of Hrd1/SYVN1 impairs ERAD, leading to accumulation of misfolded proteins, activation of the unfolded protein response, and increased ER stress, underscoring its critical function in cellular proteostasis.