Grotzke, J.E. et al. Proc. Natl. Acad. Sci. USA 110, 3393–3398 (2013).

The accumulation of misfolded proteins in a cell or organism can be catastrophic. Endoplasmic reticulum–associated degradation (ERAD) is a constitutive process that identifies misfolded proteins in the ER and shuttles them to the cytosol, where they are degraded by the proteasome. Much, however, remains to be learned about the ERAD machinery and its function. Grotzke et al. simplify the task of studying this complex pathway by developing fluorescent sensors that act as ERAD substrates. The sensors are versions of the Venus fluorescent protein that only become fluorescent after they have been first glycosylated in the ER and later deglycosylated in the cytosol through the ERAD pathway. These proteins can also be fused to additional ERAD substrates to interrogate substrate-specific pathways. Grotzke et al. used the tools in a genome-wide short interfering RNA screen to identify ERAD factors.