Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside

Chen, Guofang; Tao, Wei; Ju, Furong; Li, Haisen

doi:10.3389/fcell.2023.1156152

Cited by 7 publications

(10 citation statements)

References 259 publications

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“…Protein aggregates are known for their toxic impact on cells, disrupting crucial cellular processes by interacting with cellular membranes or sequestering essential protein complexes [ 36 , 37 ]. The accumulation of protein aggregates observed here in shCASP3-transduced cells is consistent with this result causing the observed initial delay in cell cycle progression, and decreasing cell viability and cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Dependence of human cell survival and proliferation on the CASP3 prodomain

Eskandari,

Negri,

Tan

et al. 2024

Cell Death Discov.

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Mechanisms that regulate cell survival and proliferation are important for both the development and homeostasis of normal tissue, and as well as for the emergence and expansion of malignant cell populations. Caspase-3 (CASP3) has long been recognized for its proteolytic role in orchestrating cell death-initiated pathways and related processes; however, whether CASP3 has other functions in mammalian cells that do not depend on its known catalytic activity have remained unknown. To investigate this possibility, we examined the biological and molecular consequences of reducing CASP3 levels in normal and transformed human cells using lentiviral-mediated short hairpin-based knockdown experiments in combination with approaches designed to test the potential rescue capability of different components of the CASP3 protein. The results showed that a ≥50% reduction in CASP3 levels rapidly and consistently arrested cell cycle progression and survival in all cell types tested. Mass spectrometry-based proteomic analyses and more specific flow cytometric measurements strongly implicated CASP3 as playing an essential role in regulating intracellular protein aggregate clearance. Intriguingly, the rescue experiments utilizing different forms of the CASP3 protein showed its prosurvival function and effective removal of protein aggregates did not require its well-known catalytic capability, and pinpointed the N-terminal prodomain of CASP3 as the exclusive component needed in a diversity of human cell types. These findings identify a new mechanism that regulates human cell survival and proliferation and thus expands the complexity of how these processes can be controlled.

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Section: Discussionmentioning

confidence: 99%

Dependence of human cell survival and proliferation on the CASP3 prodomain

Eskandari,

Negri,

Tan

et al. 2024

Cell Death Discov.

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“…This function is closely linked to its concentration. At high concentrations, P4HB prevents the aggregation of unfolded proteins, whereas at low concentrations, it promotes aggregation [ 49 ]. This may be relevant here as cadmium exposure decreases its abundance.…”

Section: Discussionmentioning

confidence: 99%

“…Table S4: Gene Ontology Biological Process enrichment in zebra and quagga mussel gills after cadmium exposure. Table S5: Short Summary of protein functions extracts from online database annotations [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 …”

mentioning

confidence: 99%

Cadmium Highlights Common and Specific Responses of Two Freshwater Sentinel Species, Dreissena polymorpha and Dreissena rostriformis bugensis

Bultelle,

Le Saux,

David

et al. 2024

Proteomes

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Zebra mussel (ZM), Dreissena polymorpha, commonly used as a sentinel species in freshwater biomonitoring, is now in competition for habitat with quagga mussel (QM), Dreissena rostriformis bugensis. This raises the question of the quagga mussel’s use in environmental survey. To better characterise QM response to stress compared with ZM, both species were exposed to cadmium (100 µg·L−1), a classic pollutant, for 7 days under controlled conditions. The gill proteomes were analysed using two-dimensional electrophoresis coupled with mass spectrometry. For ZM, 81 out of 88 proteoforms of variable abundance were identified using mass spectrometry, and for QM, 105 out of 134. Interestingly, the proteomic response amplitude varied drastically, with 5.6% of proteoforms of variable abundance (DAPs) in ZM versus 9.4% in QM. QM also exhibited greater cadmium accumulation. Only 12 common DAPs were observed. Several short proteoforms were detected, suggesting proteolysis. Functional analysis is consistent with the pleiotropic effects of the toxic metal ion cadmium, with alterations in sulphur and glutathione metabolisms, cellular calcium signalling, cytoskeletal dynamics, energy production, chaperone activation, and membrane events with numerous proteins involved in trafficking and endocytosis/exocytosis processes. Beyond common responses, the sister species display distinct reactions, with cellular response to stress being the main category involved in ZM as opposed to calcium and cytoskeleton alterations in QM. Moreover, QM exhibited greater evidence of proteolysis and cell death. Overall, these results suggest that QM has a weaker stress response capacity than ZM.

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“…We propose that Ste24 recognizes and fragments many of the single-pass TM proteins erroneously inserted at the ER in positive outside topology, including about half of those recognized by Spf1 and about half of those not recognized by Spf1 ( Tipper and Harley, 2002 ). We propose that the PIR quality control system complements the multiple mechanisms for eliminating misfolded ER TM proteins ( Chen et al, 2023 ). The major roles played by Spf1 and Ste24 are illustrated by their dominant roles in eliminating misfolded ER proteins ( Jonikas et al, 2009 ).…”

Section: Spf1 and Omm Protein Insertionmentioning

confidence: 99%

“…Alphafold ( Heaven, 2020 ) predicts TM protein structures well ( Hegedus et al, 2022 ) but may not yet consider the effects of membrane lipid composition. A recent review ( Chen et al, 2023 ) describes the multiple quality control systems that recognize misfolded and aggregated endoplasmic reticulum (ER) luminal proteins: the unfolded protein response (UPR) comprises ER lumen–nucleus signaling mechanisms and re-export mechanisms; the ER-associated protein degradation (ERAD) system uses multiple ER membrane ubiquitin ligases to remove proteins that escape the UPR; and the ER-associated autophagy (ER-phagy) system delivers ERAD-resistant and aggregated ER proteins to the lysosome for destruction. The proposed PIR quality control system is potentially an important additional component.…”

Section: Introductionmentioning

confidence: 99%

Spf1 and Ste24: quality controllers of transmembrane protein topology in the eukaryotic cell

Tipper

Harley

2023

Front. Cell Dev. Biol.

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DNA replication, transcription, and translation in eukaryotic cells occur with decreasing but still high fidelity. In contrast, for the estimated 33% of the human proteome that is inserted as transmembrane (TM) proteins, insertion with a non-functional inverted topology is frequent. Correct topology is essential for function and trafficking to appropriate cellular compartments and is controlled principally by responses to charged residues within 15 residues of the inserted TM domain (TMD); the flank with the higher positive charge remains in the cytosol (inside), following the positive inside rule (PIR). Yeast (Saccharomyces cerevisiae) mutants that increase insertion contrary to the PIR were selected. Mutants with strong phenotypes were found only in SPF1 and STE24 (human cell orthologs are ATP13A1 and ZMPSte24) with, at the time, no known relevant functions. Spf1/Atp13A1 is now known to dislocate to the cytosol TM proteins inserted contrary to the PIR, allowing energy-conserving reinsertion. We hypothesize that Spf1 and Ste24 both recognize the short, positively charged ER luminal peptides of TM proteins inserted contrary to the PIR, accepting these peptides into their large membrane-spanning, water-filled cavities through interaction with their many interior surface negative charges. While entry was demonstrated for Spf1, no published evidence directly demonstrates substrate entry to the Ste24 cavity, internal access to its zinc metalloprotease (ZMP) site, or active withdrawal of fragments, which may be essential for function. Spf1 and Ste24 comprise a PIR quality control system that is conserved in all eukaryotes and presumably evolved in prokaryotic progenitors as they gained differentiated membrane functions. About 75% of the PIR is imposed by this quality control system, which joins the UPR, ERAD, and autophagy (ER-phagy) in coordinated, overlapping quality control of ER protein function.

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Protein quality control and aggregation in the endoplasmic reticulum: From basic to bedside

Cited by 7 publications

References 259 publications

Dependence of human cell survival and proliferation on the CASP3 prodomain

Dependence of human cell survival and proliferation on the CASP3 prodomain

Cadmium Highlights Common and Specific Responses of Two Freshwater Sentinel Species, Dreissena polymorpha and Dreissena rostriformis bugensis

Spf1 and Ste24: quality controllers of transmembrane protein topology in the eukaryotic cell

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