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Correspondence to Markus Babst: [email protected] Abbreviations used in this paper: ART, arrestin-related trafficking adaptor; ESCRT, endosomal sorting complex required for transport; GPCR, G protein–coupled receptor; ILV, intraluminal vesicle; LID, loop interaction domain; MVB, multivesicular body; QC, quality control. Protein degradation is crucial for proper cellular function. It can fine-tune cellular pathways by reducing or eliminating the activity of a particular protein or clear away nonfunctional or dysfunctional proteins that can arise upon damage or unfolding. For the latter case, cells use numerous monitoring systems to identify unfolded proteins and trigger their rapid degradation before cell damage can occur. The best-studied systems of cellular protein quality control (QC) are those of soluble, cytoplasmic proteins. In addition, highly efficient QC systems act at the plasma membrane where the accumulation of even a few damaged transmembrane proteins could cause loss of cell integrity and death. As a consequence, cells appear to have evolved multilayered and efficient QC systems that function at different locations and use different mechanisms to ensure fidelity in the recognition of damaged proteins. This review focuses on the recent advances in the understanding how eukaryotic cells detect unfolded cell surface proteins. For more information on the pathways that function in the degradation of plasma membrane protein we refer to previously published reviews (Okiyoneda et al., 2011; MacGurn et al., 2012). A key feature of QC pathways that target soluble proteins is the recognition of unfolded proteins by molecular chaperones that bind to exposed hydrophobic regions of unfolded proteins, assist in refolding, and if refolding fails, assist in the degradation of the damaged protein (Chen et al., 2011; Kästle and Grune, 2012; Doyle et al., 2013). Guided by these insights from cytoplasmic protein QC, researchers have for many years focused on the identification of chaperone-like factors that might act similarly as sensors for unfolded transmembrane proteins at the plasma membrane. Several studies have used the model organism Saccharomyces cerevisiae due to its genetic tractability to identify quality control factors that are responsible for the rapid degradation of unfolded cell surface proteins (Li et al., 1999; Liu and Chang, 2006; Lin et al., 2008; Wang et al., 2011). Depending on the model protein and the method used for the analysis, these studies identified many factors involved in endocytosis, endosomal trafficking, and vacuolar/lysosomal degradation of cell surface proteins. In fact, these studies confirmed or identified the function of many proteins that play a role in the general degradation route for cell surface proteins, referred to as the multivesicular body (MVB) pathway (Henne et al., 2011; Hurley and Stenmark, 2011; Babst and Odorizzi, 2013), but did not identify specific quality control proteins, which shall be discussed later.