Finding the will and the way of ERAD substrate retrotranslocation

ER-associated degradation (ERAD) is a mechanism by which numerous ER-localized proteins are targeted for cytosolic degradation by the ubiquitin–proteasome system. A surprising and still-cryptic requirement of this process is the energy dependent retrotranslocation of both lumenal and membrane-embedded ER proteins into the cytosol for ongoing ubiquitination and proteasomal destruction. The current understanding, results, and open questions are discussed below for this intriguing and critical process of ERAD.