Quality control: quality control at the plasma membrane: one mechanism does not fit all

Abstract

The plasma membrane quality control system of eukaryotic cells is able to recognize and degrade damaged cell surface proteins. Recent studies have identified two mechanisms involved in the recognition of unfolded transmembrane proteins. One system uses chaperones to detect unfolded cytoplasmic domains of transmembrane proteins, whereas the second mechanism relies on an internal quality control system of the protein, which can trigger degradation when the protein deviates from the folded state. Both quality control mechanisms are key to prevent proteotoxic effects at the cell surface and to ensure cell integrity.

Figure 1.

Trafficking pathways of cell surface proteins in eukaryotic cells. Numbers refer to trafficking steps that are involved in QC. *, function in QC of transmembrane proteins has not been shown; ub, ubiquitin.

Figure 2.

Plasma membrane protein QC mechanisms. (A) Chaperones recognize unfolded cytoplasmic domains and recruit a ubiquitin ligase. Ubiquitinated proteins are rapidly endocytosed and degraded via the MVB pathway. PM, plasma membrane. (B) Nutrient transporters use the same intrinsic mechanism, the LID-degron system, for both substrate-dependent degradation and QC. Deviations from the ground state of the transporter, caused either by substrate binding or by stress (e.g., heat shock), result in ubiquitination of the degron. A moderate heat shock might trigger the conformational changes of the import cycle even in absence of substrate. Ubiquitinated transporters are rapidly endocytosed and degraded. Ubiquitination efficiency of substrate-bound transporters depends on the cytoplasmic substrate concentration (high concentrations stabilize the substrate-bound state).

Figure 3.

Possible mechanisms of ubiquitin ligase recruitment by the degron. The ubiquitin ligase might be recruited to transporters either by transmembrane adaptors, via arrestin-related trafficking adaptors (ARTs), or by direct binding to the degron region of the transporter.