Clearing Traffic Jams During Protein Translocation Across Membranes

Abstract

Protein translocation across membranes is a critical facet of protein biogenesis in compartmentalized cells as proteins synthesized in the cytoplasm often need to traverse across lipid bilayers via proteinaceous channels to reach their final destinations. It is well established that protein biogenesis is tightly linked to various protein quality control processes, which monitor errors in protein folding, modification, and localization. However, little is known about how cells cope with translocation defective polypeptides that clog translocation channels (translocons) during protein translocation. This review summarizes recent studies, which collectively reveal a set of translocon-associated quality control strategies for eliminating polypeptides stuck in protein-conducting channels in the endoplasmic reticulum and mitochondria.

The trinity of ribosome-associated quality control and stress signaling for proteostasis and neuronal physiology

“…Translation of non-cytoplasmic proteins (e.g., organellar, secretory, or membrane proteins) intrinsically accompanies ribosomal stalling during their subcellular targeting or co-translational translocation (59,60). Mammalian cells express a substantial number of mRNAs that are co-translationally translocated into ER (61,62).…”

Reduced DNAJC3 Expression Affects Protein Translocation across the ER Membrane and Attenuates the Down-Modulating Effect of the Translocation Inhibitor Cyclotriazadisulfonamide

“…The accumulation of mislocalised, misfolded and/or malfunctioning proteins due to dysfunctional protein processing (i.e., protein post-translational modifications, folding and/or assembly in the ER lumen), triggers ER stress, which is detrimental for overall cellular functions. Cells have, therefore, acquired sophisticated ER quality control processes such as the unfolded protein response (UPR) [ 21 , 22 , 23 , 24 ]. Three ER stress sensors, i.e., activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK) activate the UPR via the transcriptional upregulation of molecular chaperones to refold misfolded proteins in the ER lumen and inhibit global protein synthesis to reduce the load of client proteins, while apoptotic pathways are activated to eliminate severely damaged cells [ 21 , 22 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

“…As well as folding-related ER stress, evidence has shown that erroneously halted protein translocation also induces considerable levels of ER stress, as the partially translocated polypeptide clogs the translocon [ 24 , 60 , 61 ]. From this perspective, the retarding of protein translocation into the ER by specific Sec61 translocon inhibitors might also induce ER stress and activate cellular pathways to clear the clogged translocons.…”

“…From this perspective, the retarding of protein translocation into the ER by specific Sec61 translocon inhibitors might also induce ER stress and activate cellular pathways to clear the clogged translocons. How cells cope with clogged translocons has since emerged as an intriguing question; however, little is known about the translocon-associated quality control processes to safeguard protein translocation [ 24 ].…”

SAYSD1 senses UFMylated ribosome to safeguard co-translational protein translocation at the endoplasmic reticulum

“…In eukaryotes, proteins of the secretory pathway are synthesized by endoplasmic reticulum (ER)- bound ribosomes and inserted into the ER lumen or integrated into the membrane co-translationally through the Sec61 translocon (Rapoport et al, 2017). This process is highly sensitive to perturbations by translation stalling or defects in protein modification, folding, and assembly; all of which can generate faulty polypeptides that clog the translocon (Phillips and Miller, 2020; Wang and Ye, 2020). Failure to clear clogged translocons prevents nascent polypeptides from entering the ER, posing great harms to cells (Wang and Ye, 2020).…”