Protein quality control at the plasma membrane

Abstract

Cellular proteostasis (or protein homeostasis) depends on the timely folding and disposal of conformationally damaged polypeptides during their life span at all subcellular locations. This process is particularly important for membrane proteins confined to the cell surface with critical regulatory role in cellular homoeostasis and intercellular communication. Accumulating evidences indicate that membrane proteins exported from the endoplasmic reticulum (ER) are subjected to peripheral quality control (QC) along the late secretory and endocytic pathways, as well as at the plasma membrane (PM). Recently identified components of the PM QC recognition and effector mechanisms responsible for ubiquitination and lysosomal degradation of conformationally damaged PM proteins uncovered striking similarities to and differences from that of the ER QC machinery. Possible implications of the peripheral protein QC activity in phenotypic modulation of conformational diseases are also outlined.

Reduced PDZ Interactions of Rescued ΔF508CFTR Increases Its Cell Surface Mobility

“…S1B). These findings show in live cells that interactions with PDZ domain-containing proteins contribute to the tethering of wt and low-temperature rescued ⌬F508CFTR, but that interactions between r⌬F508CFTR 37 and PDZ domain-containing proteins are reduced compared with wtCFTR or r⌬F508CFTR 27 .…”

“…Low-temperature corrected ⌬F508CFTR has been demonstrated to interact with EBP50 (24) and mCh-CFTR-C also increased the diffusion of r⌬F508CFTR 27 (Fig. 1, C and D, orange) and r⌬F508CFTR 37 (Fig. 1, C and D, green) to the same degree as wtCFTR, suggesting that PDZ interactions contribute to the confinement of cell surface ⌬F508CFTR.…”

“…1B, middle). However, thermal unfolding of r⌬F508CFTR by 2 h of incubation at 37°C (r⌬F508CFTR 37 ), which causes accelerated endocytosis (ϳ2-fold), enhanced ubiquitination and an overall reduction in cells surface r⌬F508CFTR levels (15), produced an increase in mobility (Fig. 1B, bottom).…”

“…A, C-terminal PDZ interactions tether wtCFTR to actin (top) but their role in r⌬F508CFTR plasma membrane stability is unknown (bottom). B, individual frames from SPT image sequences acquired at 30 fps for Qdot-labeled wtCFTR (top), r⌬F508CFTR immediately after low temperature correction (r⌬F508 27 , middle) and r⌬F508CFTR after low temperature correction and subsequent incubation at 37°C for 2 h (r⌬F508 37 , bottom). Image acquisition time is given in each frame and highlighted exemplar trajectories are shown for each condition (right, 200 nm scale bar refers to all trajectories).…”

Ubiquitin-Dependent Sorting in Endocytosis

“…Besides CHIP, other Ub ligases can recognize non-native polypeptides via chaperone interactions. These include Ubr1/2, UBE3A, and Cul5; however, their contribution to plasma membrane quality control has not been addressed (Okiyoneda et al 2011). There are also precedents for chaperone-independent recognition of non-native client protein as exemplified by CHIP, Hrd1, and San1 activity in the cytoplasm, ER, and nucleus, respectively (Rosser et al 2007;Kanehara et al 2010;Rosenbaum et al 2011).…”