endoplasmic reticulum associated degradation
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mBio ◽  
2022 ◽  
Author(s):  
Poulami Das ◽  
Wendy Kaichun Xu ◽  
Amit Kumar Singh Gautam ◽  
Mary M. Lozano ◽  
Jaquelin P. Dudley

Endoplasmic reticulum-associated degradation (ERAD) is a form of cellular protein quality control that is manipulated by viruses, including the betaretrovirus, mouse mammary tumor virus (MMTV). MMTV-encoded signal peptide (SP) has been shown to interact with an essential ERAD factor, VCP/p97 ATPase, to mediate its extraction from the ER membrane, also known as retrotranslocation, for RNA binding and nuclear function.


2021 ◽  
Author(s):  
Patrick G Needham ◽  
Jennifer L Goeckeler-Fried ◽  
Casey Zhang ◽  
Zhihao Sun ◽  
Adam R Wetzel ◽  
...  

SLC26A9, a member of the solute carrier protein family, transports chloride ions across various epithelia. SLC26A9 also associates with other ion channels and transporters linked to human health, and in some cases these heterotypic interactions are essential to support the biogenesis of both proteins. Therefore, understanding how this complex membrane protein is initially folded might provide new therapeutic strategies to overcome deficits in the function of SLC26A9 partners, one of which is associated with Cystic Fibrosis. To this end, we developed a novel yeast expression system for SLC26A9. This facile system has been used extensively with other ion channels and transporters to screen for factors that oversee protein folding checkpoints. As commonly observed for other channels and transporters, we first noted that a substantial fraction of SLC26A9 is targeted for endoplasmic reticulum associated degradation (ERAD), which destroys folding-compromised proteins in the early secretory pathway. We next discovered that ERAD selection requires the Hsp70 chaperone, which can play a vital role in ERAD substrate selection. We then created SLC26A9 mutants and found that the transmembrane-rich domain of SLC26A9 was quite stable, whereas the soluble cytosolic STAS domain was responsible for Hsp70-dependent ERAD. To support data obtained in the yeast model, we were able to recapitulate Hsp70-facilitated ERAD of the STAS domain in human tissue culture cells. These results indicate that a critical barrier to nascent membrane protein folding can reside within a specific soluble domain, one that is monitored by components associated with the ERAD machinery.


2021 ◽  
Author(s):  
Yi-Shi Liu ◽  
Yicheng Wang ◽  
Xiaoman Zhou ◽  
LinPei Zhang ◽  
Ganglong Yang ◽  
...  

Abstract We previously reported that glycosylphosphatidylinositol (GPI) biosynthesis is regulated by endoplasmic reticulum associated degradation (ERAD); however, the underlying mechanistic basis remains unclear. Based on a genome-wide CRISPR–Cas9 screen, we show that a widely expressed GPI-anchored protein CD55 precursor and ER-resident ARV1 together upregulate GPI biosynthesis under ERAD-deficient conditions. In cells defective in GPI transamidase, GPI-anchored protein precursors fail to obtain GPI, remaining the uncleaved GPI-attachment signal at the C-termini. We show that ERAD deficiency causes accumulation of the CD55 precursor, which in turn upregulates GPI biosynthesis, where the GPI-attachment signal peptide is the active element. Among the 32 GPI-anchored proteins tested, only the GPI-attachment signal peptides of CD55 and CD48 enhance GPI biosynthesis. ARV1 is essential for the GPI upregulation by CD55 precursor. Our data demonstrate an ARV1-dependent regulatory connection between GPI biosynthesis and precursors of select GPI-anchored proteins that are under the control of ERAD.


2021 ◽  
Author(s):  
Juan Zhang ◽  
Jin-Cai Wang ◽  
Yue Shang ◽  
Yang Chen ◽  
Shu-Zhen Chen ◽  
...  

Abstract Boningmycin (BON), a new member of the bleomycin family, exhibits highly potent activity against tumor cells in vitro and in vivo. It remains unclear if BON can affect the protein levels of programmed death ligand-1 (PD-L1) in a manner similar to that of other antitumor agents. Potent inhibition of cell survival by BON was observed in non-small-cell lung cancer NCI-H460 cells and sarcoma HT1080 cells. Apoptosis-independent reduction of PD-L1 was observed after exposure to BON. Furthermore, BON-treatment increased AMP-activated protein kinase phosphorylation, however, this increase was suppressed by treatment with specific inhibitor (compound C) or RNAi-mediated knockdown of AMPKα. BON-induced PD-L1 reduction is mediated by the endoplasmic reticulum-associated degradation pathway. Its mode of action is similar to that of metformin on the PD-L1 protein. In conclusion, it is firstly reported that BON can decrease PD-L1 protein levels through the AMPK activated endoplasmic reticulum- associated degradation pathway.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ginto George ◽  
Satoshi Ninagawa ◽  
Hirokazu Yagi ◽  
Jun-ichi Furukawa ◽  
Noritaka Hashii ◽  
...  

Sequential mannose trimming of N-glycan, from M9 to M8B and then to oligosaccharides exposing the a1,6-linked mannosyl residue (M7A, M6 and M5), facilitates endoplasmic reticulum-associated degradation of misfolded glycoproteins (gpERAD). We previously showed that EDEM2 stably disulfide-bonded to the thioredoxin domain-containing protein TXNDC11 is responsible for the first step (George et al., 2020). Here, we show that EDEM3 and EDEM1 are responsible for the second step. Incubation of pyridylamine-labeled M8B with purified EDEM3 alone produced M7 (M7A and M7C), M6 and M5. EDEM1 showed a similar tendency, although much lower amounts of M6 and M5 were produced. Thus, EDEM3 is a major a1,2-mannosidase for the second step from M8B. Both EDEM3 and EDEM1 trimmed M8B from a glycoprotein efficiently. Our confirmation of the Golgi localization of MAN1B indicates that no other a1,2-mannosidase is required for gpERAD. Accordingly, we have established the entire route of oligosaccharide processing and the enzymes responsible.


2021 ◽  
Author(s):  
Tianqi Guo ◽  
Henriette Weber ◽  
Michael C.E. Niemann ◽  
Lisa Theisl ◽  
Ondřej Novák ◽  
...  

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