In 2004 the DERL1 gene was discovered independently by two research groups when they were exploring the machinery of retrotranslocation in the ER in the cell. One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Horward Medical School, Boston, Massachusetts. Another evidence of the DERL1 gene was discovered by Professor Hidde L. Ploegh and his research group who is also at Horward Medical School, Boston, Massachusetts. As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996, it was named after the yeast gene.
Under ER stress, the carboxyl-terminus region of derlin-1 captures specific misfolded proteins in the ER lumen. Derlin-1 also interacts with VIMP, an ER membrane protein that recruits the cytosolic ATPase p97 and its cofactor. The interaction of derlin-1 with p97 via VIMP is essential for export of misfolded proteins. p97 is required for the transport of the misfolded proteins through the ER membrane and back to the cytosolic side for their degradation. This process is referred to as retrotranslocation. Hence, one of the functions of derlin-1 is to reroute specific misfolded protein to the cytosol for their degradation. Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase. This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS). Currently, the molecular mechanism by which derlin-1 reroutes the misfolded proteins from ER to their degradation are not fully understood.
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