Control of Protein Homeostasis in the Early Secretory Pathway: Current Status and Challenges DOI Creative Commons
Daria Sicari, Aeid Igbaria, Éric Chevet

и другие.

Cells, Год журнала: 2019, Номер 8(11), С. 1347 - 1347

Опубликована: Окт. 29, 2019

Discrimination between properly folded proteins and those that do not reach this state is necessary for cells to achieve functionality. Eukaryotic have evolved several mechanisms ensure secretory protein quality control, which allows efficiency fidelity in production. Among the actors involved such process, both endoplasmic reticulum (ER) Golgi complex play prominent roles synthesis, biogenesis secretion. ER functions only are allowed flow through pathway while improperly be eliminated impinge on cellular functions. Thus, control degradation machineries crucial prevent toxic accumulation of proteins. However, some instances, can escape systems thereby contributing human diseases. Herein, we summarize how early pathways copes with proteins, insufficient handling cause development Finally, detail genetic pharmacologic approaches could used as potential therapeutic tools treat these

Язык: Английский

ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum DOI Creative Commons
Fulvio Reggiori, Maurizio Molinari

Physiological Reviews, Год журнала: 2022, Номер 102(3), С. 1393 - 1448

Опубликована: Фев. 21, 2022

ER-phagy (reticulophagy) defines the degradation of portions endoplasmic reticulum (ER) within lysosomes or vacuoles. It is part self-digestion (i.e., autophagic) programs recycling cytoplasmic material and organelles, which rapidly mobilize metabolites in cells confronted with nutrient shortage. Moreover, selective clearance ER subdomains participates control size activity during stress, reestablishment homeostasis after stress resolution, removal parts aberrant potentially cytotoxic has been segregated. relies on individual and/or concerted activation receptors, peripheral integral membrane proteins that share presence LC3/Atg8-binding motifs their cytosolic domains. involves physical separation from bulk network delivery to endolysosomal/vacuolar catabolic district. This last step accomplished by a variety mechanisms including macro-ER-phagy (in fragments are sequestered double-membrane autophagosomes eventually fuse lysosomes/vacuoles), micro-ER-phagy directly engulfed endosomes/lysosomes/vacuoles), direct fusion ER-derived vesicles lysosomes/vacuoles. dysfunctional specific human diseases, its regulators subverted pathogens, highlighting crucial role for cell organism life.

Язык: Английский

Процитировано

113
Order through destruction: how ER‐associated protein degradation contributes to organelle homeostasis DOI Creative Commons
John C. Christianson, Pedro Carvalho

The EMBO Journal, Год журнала: 2022, Номер 41(6)

Опубликована: Фев. 16, 2022

The endoplasmic reticulum (ER) is a large, dynamic, and multifunctional organelle. ER protein homeostasis essential for the coordination of its diverse functions depends on ER-associated degradation (ERAD). latter process selects target proteins in lumen membrane ER, promotes their ubiquitination, facilitates delivery into cytosol by proteasome. Originally characterized role misfolded rate-limiting enzymes sterol biosynthesis, many branches ERAD now appear to control levels wider range substrates influence more broadly organization as well interactions with adjacent organelles. Here, we discuss recent mechanistic advances our understanding consequences regulation functions.

Язык: Английский

Процитировано

95
Cellular functions and molecular mechanisms of non-lysine ubiquitination DOI Creative Commons
Amie J. McClellan, Sophie Heiden Laugesen, Lars Ellgaard

и другие.

Open Biology, Год журнала: 2019, Номер 9(9), С. 190147 - 190147

Опубликована: Сен. 1, 2019

Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical takes place on lysine residues, but the past 15 years non-lysine serine, threonine cysteine has been firmly established. With emerging ubiquitination, it crucial to identify responsible molecular machinery understand mechanistic basis for ubiquitination. Here, we first provide an overview literature that documented Informed by these examples, then discuss mechanisms implications conclude outlining open questions future perspectives field.

Язык: Английский

Процитировано

145
UFMylation of RPL26 links translocation-associated quality control to endoplasmic reticulum protein homeostasis DOI Open Access

Lihui Wang,

Yue Xu,

Heather Rogers

и другие.

Cell Research, Год журнала: 2019, Номер 30(1), С. 5 - 20

Опубликована: Окт. 8, 2019

Язык: Английский

Процитировано

139
Proteasomal and lysosomal clearance of faulty secretory proteins: ER-associated degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD) pathways DOI
Ilaria Fregno, Maurizio Molinari

Critical Reviews in Biochemistry and Molecular Biology, Год журнала: 2019, Номер 54(2), С. 153 - 163

Опубликована: Март 4, 2019

About 40% of the eukaryotic cell's proteins are inserted co- or post-translationally in endoplasmic reticulum (ER), where they attain native structure under assistance resident molecular chaperones and folding enzymes. Subsequently, these secreted from cells transported to their sites function at plasma membrane organelles secretory endocytic compartments. Polypeptides that not delivered within ER (mis-localized proteins, MLPs) rapidly destroyed by cytosolic proteasomes, with intervention protease ZMPSTE24 if remained trapped SEC61 translocation machinery. Proteins enter ER, but fail degraded prevent toxic accumulation aberrant gene products. The does contain degradative devices majority misfolded generated this biosynthetic compartment dislocated across for degradation 26S proteasomes mechanisms pathways collectively defined as ER-associated (ERAD). do engage ERAD factors, aggregates polymers, too large, display chimico/physical features dislocation (ERAD-resistant proteins) endo-lysosome clearance, ER-to-lysosomes-associated (ERLAD). Emerging evidences lead us propose ERLAD an umbrella term includes autophagic non-autophagic activated engaged ERAD-resistant delivery endo-lysosomes.

Язык: Английский

Процитировано

133
Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway DOI Creative Commons
Bingtian Xu,

Yunyun Qin,

Dan Li

и другие.

Redox Biology, Год журнала: 2019, Номер 28, С. 101342 - 101342

Опубликована: Окт. 13, 2019

Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative is an inducer ER stress. The present study aimed to determine whether suppression in protective PDE4 inhibition We found that exposing HT-22 cells oxygen-glucose deprivation (OGD) significantly activated stress, as evidenced by increased expression 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), C/EBP-homologous (CHOP). Overexpression PDE4B while knocking down or treatment with inhibitor, FCPR03, prevented OGD-induced cells. Furthermore, FCPR03 promoted translocation nuclear erythroid 2-related 2 (Nrf-2) from cytoplasm nucleus. Importantly, Nrf-2 ML385, blocked inhibitory role on ML385 also abolished subjected OGD. Knocking heme oxygenase-1 (HO-1), which a target Nrf-2, enhanced level reactive oxygen species (ROS), cell death. then antioxidant, N-Acetyl-l-cysteine, reduced exposed This effect was accompanied viability decreased In primary cultured neurons, we production ROS phosphorylation eIF2α. OGD neurons ML385. These results demonstrate activates Nrf-2/HO-1, attenuates ROS, thereby Additionally, conclude may represent promising therapeutic agent for stress-related disorders.

Язык: Английский

Процитировано

103
ER-phagy responses in yeast, plants, and mammalian cells and their crosstalk with UPR and ERAD DOI Creative Commons
Maurizio Molinari

Developmental Cell, Год журнала: 2021, Номер 56(7), С. 949 - 966

Опубликована: Март 24, 2021

Язык: Английский

Процитировано

92
Squalene monooxygenase: a journey to the heart of cholesterol synthesis DOI
Ngee Kiat Chua, Hudson W. Coates, Andrew J. Brown

и другие.

Progress in Lipid Research, Год журнала: 2020, Номер 79, С. 101033 - 101033

Опубликована: Апрель 28, 2020

Язык: Английский

Процитировано

86
Cell-Nonautonomous Regulation of Proteostasis in Aging and Disease DOI Open Access
Richard I. Morimoto

Cold Spring Harbor Perspectives in Biology, Год журнала: 2019, Номер 12(4), С. a034074 - a034074

Опубликована: Апрель 8, 2019

The functional health of the proteome is determined by properties proteostasis network (PN) that regulates protein synthesis, folding, macromolecular assembly, translocation, and degradation. In eukaryotes, PN also integrates biogenesis across compartments within cell between tissues metazoans for organismal longevity. Additionally, in metazoans, stability proteins optimized development yet declines throughout aging, accelerating risk misfolding, aggregation, cellular dysfunction. Here, I describe cell-nonautonomous regulation tissue communication stress-response pathways. These systems are robust from through reproductive maturity genetically programmed to decline abruptly early adulthood repression heat shock response other cell-protective stress responses, thus compromising ability cells properly buffer against cumulative damage during aging. While failure multiple quality control processes aging challenges function health, genetic studies, identification small-molecule regulators suggests strategies can be employed reset with potential benefit on

Язык: Английский

Процитировано

85
Glucose metabolism and AD: evidence for a potential diabetes type 3 DOI Creative Commons
Andrea González, Camila Calfío, Macarena Churruca

и другие.

Alzheimer s Research & Therapy, Год журнала: 2022, Номер 14(1)

Опубликована: Апрель 20, 2022

Alzheimer's disease is the most prevalent cause of dementia in elderly. Neuronal death and synaptic dysfunctions are considered main hallmarks this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated a key regulatory element onset progression AD, which why nowadays AD type 3 diabetes.

Язык: Английский

Процитировано

63