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

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: April 19, 2023

Endoplasmic reticulum (ER) is the largest membrane-bound compartment in all cells and functions as a key regulator protein biosynthesis, lipid metabolism, calcium balance. Mammalian endoplasmic has evolved with an orchestrated quality control system to handle defective proteins ensure homeostasis. Nevertheless, accumulation aggregation of misfolded may occur during pathological conditions. The inability clear faulty aggregates from results development many human disorders. efforts comprehensively understand network will benefit diagnostics therapeutics storage diseases. Herein, we overview recent advances mammalian system, describe phase transition model, summarize approaches monitor aggregation. Moreover, discuss therapeutic applications enhancing pathways

Language: Английский

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RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 7, 2024

Abstract The toll-like receptor 4 (TLR4) is a central regulator of innate immunity that primarily recognizes bacterial lipopolysaccharide cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as negative TLR4 signaling. show triggers degradation TLR4’s trafficking factor TMED7. This counteracts transport surface. Notably, activation mediates transcriptional upregulation thereby inducing feedback loop reduce plasma membrane. secretory cargo tuning mechanism prevents over-activation TLR4-dependent signaling in an vitro Mycobacterium tuberculosis macrophage infection model and consequently alleviates septic shock mouse model. A hypomorphic mutation linked Kawasaki syndrome, ill-defined inflammatory disorder children, further supports pathophysiological relevance our findings. In this work, we RHBDL4-mediated axis acts rheostat prevent pathway.

Language: Английский

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Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity

Science Immunology, Journal Year: 2024, Volume and Issue: 9(101)

Published: Nov. 15, 2024

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in exhaustion. However, little known about the mechanisms regulate TIM-3 surface expression turnover. Here, we report human palmitoylated by palmitoyltransferase DHHC9 at residue cysteine 296 (Cys

Language: Английский

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Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 9, 2024

Abstract Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, metabolic regulation, are determined by ER-resident MARCH6 ligases, including Doa10 yeast. Here, we present Doa10/MARCH6 structural analysis cryo-EM AlphaFold predictions, a structure-based mutagenesis campaign. The majority of adopts unique circular structure within the membrane. This channel is established lipid-binding scaffold, gated flexible helical bundle. ubiquitylation active site positioned over connections between cytosolic ligase RING domain membrane-spanning scaffold gate. assaying 95 variants for effects on stability well-characterized substrate SQLE, which regulates cholesterol levels, reveal consistent with AlphaFold-models substrate-engaged complexes. SQLE degradation further depends domain, lipid binding sites, revealing how interconnected elements could orchestrate signals, binding, activity.

Language: Английский

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Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(1), P. 6 - 20

Published: Jan. 31, 2024

The endoplasmic reticulum, a key cellular organelle, regulates wide variety of activities. Endoplasmic reticulum autophagy, one the quality control systems plays pivotal role in maintaining homeostasis by controlling turnover, remodeling, and proteostasis. In this review, we briefly describe system, subsequently focus on emphasizing spatial temporal mechanisms underlying regulation autophagy according to requirements. We also summarize evidence relating how defective or abnormal contributes pathogenesis neurodegenerative diseases. summary, review highlights associated with they influence pathophysiology degenerative nerve disorders. This would help researchers understand roles regulatory reticulum-phagy

Language: Английский

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The Epstein-Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and reticulophagy

Autophagy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 23

Published: Jan. 22, 2025

The synthesis of membrane and secreted proteins is safeguarded by an endoplasmic reticulum-associated ribosome quality control (ER-RQC) that promotes the disposal defective translation products proteasome or via a lysosome-dependent pathway involving degradation portions ER macroautophagy (reticulophagy). UFMylation RPL26 on ER-stalled ribosomes essential for activating ER-RQC reticulophagy. Here, we report viral deubiquitinase (vDUB) encoded in N-terminal domain Epstein-Barr virus (EBV) large tegument protein BPLF1 hinders stall at ER, stabilization substrates, inhibits vDUB did not act as de-UFMylase interfere with CYB5R3 UFL1 ligase. Instead, it copurified sucrose gradients abrogated ZNF598- LTN1-independent ubiquitination event required UFMylation. Physiological levels impaired productively EBV-infected cells, pointing to important role enzyme regulating allows efficient production infectious virus.

Language: Английский

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Lysosomal degradation of ER client proteins by ER-phagy and related pathways

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169035 - 169035

Published: Feb. 1, 2025

The endoplasmic reticulum (ER) is a major site of cellular protein synthesis. Degradation overabundant, misfolded, aggregating or unwanted proteins required to maintain proteostasis and avoid the deleterious consequences aberrant accumulation, at organismal level. While extensive research has shown an important role for proteasomally-mediated, ER-associated degradation (ERAD) in maintaining proteostasis, it becoming clear that there substantial lysosomal "client" from ER lumen membrane (ER-to-lysosome degradation, ERLAD). Here we provide brief overview broad categories ERLAD - predominantly ER-phagy (ER autophagy) pathways related processes. We collate client known date, either individual species proteins. Where known, summarise molecular mechanisms by which they are selected setting client(s) correct cell tissue function. Finally, highlight questions remain open this area.

Language: Английский

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Regulated degradation of the inner nuclear membrane protein SUN2 maintains nuclear envelope architecture and function

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Nov. 1, 2022

Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) inner membrane (INM) proteins. Mutations in INM proteins interfering with these result disease. However, mechanisms controlling the levels turnover of remain unknown. Here, we describe a mechanism regulated degradation SUN domain-containing protein 2 (SUN2). We show that Casein Kinase C-terminal domain Envelope Phosphatase 1 (CTDNEP1) have opposing effects SUN2 by regulating binding to ubiquitin ligase Skp/Cullin1/F-Box βTrCP (SCF ). Upon phosphorylated SUN2, SCF promotes its ubiquitination. Ubiquitinated is extracted AAA ATPase p97 delivered proteasome for degradation. Importantly, accumulation non-degradable results aberrant architecture, vulnerability DNA damage increased lagging chromosomes mitosis. These findings uncover central role proteolysis homeostasis.

Language: Английский

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Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 64, P. 100853 - 100853

Published: July 8, 2022

Language: Английский

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Rhomboid protease RHBDL4 promotes retrotranslocation of aggregation-prone proteins for degradation

Cell Reports, Journal Year: 2022, Volume and Issue: 40(6), P. 111175 - 111175

Published: Aug. 1, 2022

Protein degradation is fundamentally important to ensure cell homeostasis. In the endoplasmic reticulum (ER), ER-associated (ERAD) pathway targets incorrectly folded and unassembled proteins for turnover by cytoplasmic proteasome. Previously, we showed that rhomboid protease RHBDL4, together with p97, mediates membrane protein degradation. However, whether RHBDL4 acts in concert additional ERAD components unclear, its full substrate spectrum remains be defined. Here, show that, addition proteins, cleaves aggregation-prone luminal substrates. Since mutations of domain led stabilization substrates at side, hypothesize analogous homolog factor derlin, directly involved retrotranslocation. RHBDL4's interaction erlin complex reciprocal erlins suggest form a clips thereby rescues peptides ER from aggregation.

Language: Английский

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