Updated project metadata. Forward genetic screens in human cells we find that the proteasome-mediated degradation of the soluble misfolded reporter, mCherry-CL1, involves two ER-resident E3 ligases, MARCH6 and TRC8. To identify a more physiological correlate we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail-anchored protein Heme-Oxygenase-1 (HO-1).