Protein misfolding occurring in the endoplasmic reticulum (ER) might eventually lead to aggregation and cellular distress, and is a primary pathogenic mechanism in multiple human disorders. Mammals ...have developed evolutionary‐conserved quality control mechanisms at the level of the ER. The best characterized is the ER‐associated degradation (ERAD) pathway, through which misfolded proteins translocate from the ER to the cytosol and are subsequently proteasomally degraded. However, increasing evidence indicates that additional quality control mechanisms apply for misfolded ER clients that are not eligible for ERAD. This review focuses on the alternative, ERAD‐independent, mechanisms of clearance of misfolded polypeptides from the ER. These processes, collectively referred to as ER‐to‐lysosome–associated degradation, involve ER‐phagy, microautophagy or vesicular transport. The identification of the underlying molecular mechanisms is particularly important for developing new therapeutic approaches for human diseases associated with protein aggregate formation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ER-phagy, literally endoplasmic reticulum (ER)-eating, defines the constitutive or regulated clearance of ER portions within metazoan endolysosomes or yeast and plant vacuoles. The advent of electron ...microscopy led to the first observations of ER-phagy over 60 years ago, but only recently, with the discovery of a set of regulatory proteins named ER-phagy receptors, has it been dissected mechanistically. ER-phagy receptors are activated by a variety of pleiotropic and ER-centric stimuli. They promote ER fragmentation and engage luminal, membrane-bound, and cytosolic factors, eventually driving lysosomal clearance of select ER domains along with their content. After short historical notes, this review introduces the concept of ER-phagy responses (ERPRs). ERPRs ensure lysosomal clearance of ER portions expendable during nutrient shortage, nonfunctional, present in excess, or containing misfolded proteins. They cooperate with unfolded protein responses (UPRs) and with ER-associated degradation (ERAD) in determining ER size, function, and homeostasis.
ER-phagy, literally endoplasmic reticulum (ER)-eating, defines the constitutive or regulated clearance of ER portions within eukaryotic cells. In this review, Molinari examines how ER-phagy responses (ERPRs) collaborate with unfolded protein responses (UPRs) to regulate the lysosomal clearance of ER portions and thereby determine ER size and function.
Conserved catabolic pathways operate to remove aberrant polypeptides from the endoplasmic reticulum (ER), the major biosynthetic organelle of eukaryotic cells. The best known are the ER‐associated ...degradation (ERAD) pathways that control the retrotranslocation of terminally misfolded proteins across the ER membrane for clearance by the cytoplasmic ubiquitin/proteasome system. In this review, we catalog folding‐defective mammalian, yeast, and plant proteins that fail to engage ERAD machineries. We describe that they rather segregate in ER subdomains that eventually vesiculate. These ER‐derived vesicles are captured by double membrane autophagosomes, engulfed by endolysosomes/vacuoles, or fused with degradative organelles to clear cells from their toxic cargo. These client‐specific, mechanistically diverse ER‐phagy pathways are grouped under the umbrella term of ER‐to‐lysosome‐associated degradation for description in this essay.
Endoplasmic reticulum‐associated degradation (ERAD) pathways control the retrotranslocation of terminally misfolded proteins across the ER membrane for clearance by the cytoplasmic ubiquitin/proteasome system. ER‐to‐lysosome‐associated degradation (ERLAD) pathways remove ERAD‐resistant proteins that are segregated into ER subdomains and transported to degradative compartments via mechanistically diverse ER‐phagy routes. Here, we provide an inventory of mammalian, yeast, and plant ERLAD clients and client‐specific ER‐phagy mechanisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
About 40% of the eukaryotic cell's proteins are inserted co- or post-translationally in the endoplasmic reticulum (ER), where they attain the native structure under the assistance of resident ...molecular chaperones and folding enzymes. Subsequently, these proteins are secreted from cells or are transported to their sites of function at the plasma membrane or in organelles of the secretory and endocytic compartments. Polypeptides that are not delivered within the ER (mis-localized proteins, MLPs) are rapidly destroyed by cytosolic proteasomes, with intervention of the membrane protease ZMPSTE24 if they remained trapped in the SEC61 translocation machinery. Proteins that enter the ER, but fail to attain the native structure are rapidly degraded to prevent toxic accumulation of aberrant gene products. The ER does not contain degradative devices and the majority of misfolded proteins generated in this biosynthetic compartment are dislocated across the membrane for degradation by cytosolic 26S proteasomes by mechanisms and pathways collectively defined as ER-associated degradation (ERAD). Proteins that do not engage ERAD factors, that enter aggregates or polymers, are too large, display chimico/physical features that prevent dislocation across the ER membrane (ERAD-resistant misfolded proteins) are delivered to endo-lysosome for clearance, by mechanisms and pathways collectively defined as ER-to-lysosomes-associated degradation (ERLAD). Emerging evidences lead us to propose ERLAD as an umbrella term that includes the autophagic and non-autophagic pathways activated and engaged by ERAD-resistant misfolded proteins generated in the ER for delivery to degradative endo-lysosomes.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining ...cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress‐mediated autophagy and ER‐phagy. The ER stress‐mediated autophagy is characterized by the generation of autophagosomes that include worn‐out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER‐phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER. The signaling pathways of IRE1α, PERK, ATF6, and Ca2+ are necessary for the activation of ER stress‐mediated autophagy, while the receptor‐mediated selective ER‐phagy degrades the ER is Atg40/FAM134B. The ER stress‐mediated autophagy and ER‐phagy not only have differences, but also have connections. The activation of ER‐phagy requires the core autophagy machinery, and the ER‐phagy may be a branch of ER stress‐mediated autophagy that selectively targets the ER. However, the determined factors that control the changeover switch between ER stress‐mediated autophagy and ER‐phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation. This review summarized the crosstalk between ER stress‐mediated autophagy and ER‐phagy and their signaling networks. Additionally, we discussed the possible factors that influence the type of autophagy induced by ER stress.
Under ER stress condition, the ER stress‐mediated autophagy and ER‐phagy can be activated, and both involved in UPR and the core autophagy machinery. However, the determined factors that control the changeover switch between ER stress‐mediated autophagy and ER‐phagy, are unclear. And we speculate that the type of cells and the extent of stimulation may be associated with the type of autophagy induced by ER stress.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic ...degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.
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•The autophagic adaptor p62 mediates autophagic degradation of the ER (ER-phagy)•The ER membrane E3 ligase TRIM13 is a ubiquitin-dependent ER-phagy receptor to p62•N-terminal arginylation is an ER-phagy degron via binding to the ZZ domain of p62•p62-TRIM13-Nt-Arg circuit mediates ER protein quality control and homeostasis
Ji et al. show that the N-degron pathway mediates ER-phagy for ER protein quality control, initiated by the interaction of the autophagic cargo adaptor p62 and the transmembrane E3 ligase TRIM13. Ubiquitination of TRIM13 and the N-terminal arginine residue of N-degron substrates such as BiP/GRP78 function as ER-phagy degrons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Objectives
Pathologic complete response (pCR) rate after neoadjuvant chemotherapy was compared between 141 estrogen receptor (ER)–negative (43%), 41 low ER+ (13%), 47 moderate ER+ (14%), and ...98 high ER+ (30%) tumors.
Methods
Human epidermal growth factor receptor 2–positive cases, cases without semiquantitative ER score, and patients treated with neoadjuvant endocrine therapy alone were excluded.
Results
The pCR rate of low ER+ tumors was similar to the pCR rate of ER– tumors (37% and 26% for low ER and ER– respectively, P = .1722) but significantly different from the pCR rate of moderately ER+ (11%, P = .0049) and high ER+ tumors (4%, P < .0001). Patients with pCR had an excellent prognosis regardless of the ER status. In patients with residual disease (no pCR), the recurrence and death rate were higher in ER– and low ER+ cases compared with moderate and high ER+ cases.
Conclusions
Low ER+ breast cancers are biologically similar to ER– tumors. Semiquantitative ER H-score is an important determinant of response to neoadjuvant chemotherapy.
Autophagic degradation of the endoplasmic reticulum (ER-phagy) is triggered by ER stress in diverse organisms. However, molecular mechanisms governing ER stress-induced ER-phagy remain insufficiently ...understood. Here we report that ER stress-induced ER-phagy in the fission yeast Schizosaccharomyces pombe requires Epr1, a soluble Atg8-interacting ER-phagy receptor. Epr1 localizes to the ER through interacting with integral ER membrane proteins VAPs. Bridging an Atg8-VAP association is the main ER-phagy role of Epr1, as it can be bypassed by an artificial Atg8-VAP tether. VAPs contribute to ER-phagy not only by tethering Atg8 to the ER membrane, but also by maintaining the ER-plasma membrane contact. Epr1 is upregulated during ER stress by the unfolded protein response (UPR) regulator Ire1. Loss of Epr1 reduces survival against ER stress. Conversely, increasing Epr1 expression suppresses the ER-phagy defect and ER stress sensitivity of cells lacking Ire1. Our findings expand and deepen the molecular understanding of ER-phagy.
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•Epr1 is a soluble ER-phagy receptor critical for ER stress-induced ER-phagy•The main role of Epr1 is to bridge the association between Atg8 and VAPs•VAP-mediated ER-plasma membrane contact is important for ER stress-induced ER-phagy•UPR regulator Ire1 contributes to ER stress-induced ER-phagy by upregulating Epr1
Zhao et al. show that the fission yeast protein Epr1 confers resistance to ER stress by promoting the autophagic degradation of the ER (ER-phagy). Epr1 acts as a bridging molecule to mediate the association between Atg8 on the autophagic membrane and the integral membrane proteins VAPs on the ER.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Maintenance of cellular proteostasis relies on efficient clearance of defective gene products. For misfolded secretory proteins, this involves dislocation from the endoplasmic reticulum (ER) into the ...cytosol followed by proteasomal degradation. However, polypeptide aggregation prevents cytosolic dislocation and instead activates ill‐defined lysosomal catabolic pathways. Here, we describe an ER‐to‐lysosome‐associated degradation pathway (ERLAD) for proteasome‐resistant polymers of alpha1‐antitrypsin Z (ATZ). ERLAD involves the ER‐chaperone calnexin (CNX) and the engagement of the LC3 lipidation machinery by the ER‐resident ER‐phagy receptor FAM134B, echoing the initiation of starvation‐induced, receptor‐mediated ER‐phagy. However, in striking contrast to ER‐phagy, ATZ polymer delivery from the ER lumen to LAMP1/RAB7‐positive endolysosomes for clearance does not require ER capture within autophagosomes. Rather, it relies on vesicular transport where single‐membrane, ER‐derived, ATZ‐containing vesicles release their luminal content within endolysosomes upon membrane:membrane fusion events mediated by the ER‐resident SNARE STX17 and the endolysosomal SNARE VAMP8. These results may help explain the lack of benefits of pharmacologic macroautophagy enhancement that has been reported for some luminal aggregopathies.
Synopsis
Misfolded proteins in the endoplasmic reticulum (ER) are dislocated across the ER membrane and degraded by the ubiquitin‐proteasome‐system. Proteasome‐resistant alpha1‐antitrypsin Z (ATZ) misfolded polymers undergo a novel ER‐to‐lysosome clearance pathway that requires ER‐phagy components, vesicular traffic and endolysosome fusion.
ATZ polymers are delivered from the ER to endolysosomal degradative compartments via receptor‐mediated vesicular traffic.
The ER‐chaperone Calnexin segregates ATZ polymers in ER subdomains and in ER‐derived vesicles under the control of ER‐phagy receptor FAM134B.
ATZ‐loaded vesicles recruit LC3 to dock and fuse with endolysosomes, leading to degradation of the ATZ polymers.
ER‐resident Syntaxin‐17 and lysosomal SNARE VAMP8 mediate membrane fusion events to guide allow degradation of misfolded polymers.
Clearance of proteasome‐resistant protein aggregates from the endoplasmic reticulum requires components of the LC3 lipidation machinery but occurs independently of autophagosome formation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The ability of cells to perceive and respond to mechanical cues is essential for numerous biological activities. Emerging evidence indicates important contributions of organelles to cellular ...mechanosensitivity and mechanotransduction. However, whether and how the endoplasmic reticulum (ER) senses and reacts to mechanical forces remains elusive. To fill the knowledge gap, after developing a light-inducible ER-specific mechanostimulator (LIMER), we identify that mechanostimulation of ER elicits a transient, rapid efflux of Ca2+ from ER in monkey kidney COS-7 cells, which is dependent on the cation channels transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and polycystin-2 (PKD2) in an additive manner. This ER Ca2+ release can be repeatedly stimulated and tuned by varying the intensity and duration of force application. Moreover, ER-specific mechanostimulation inhibits ER-to-Golgi trafficking. Sustained mechanostimuli increase the levels of binding-immunoglobulin protein (BiP) expression and phosphorylated eIF2α, two markers for ER stress. Our results provide direct evidence for ER mechanosensitivity and tight mechanoregulation of ER functions, placing ER as an important player on the intricate map of cellular mechanotransduction.
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•We developed an optogenetic ER-specific mechanostimulator, LIMER•We revealed mechanosensitivity of ER and tight mechanoregulation of ER functions•ER mechanostimulation elicits Ca2+ efflux from ER via TRPV1 and PKD2 channels•It inhibits ER-to-Golgi trafficking and increases levels of ER stress markers
Song et al. present an ER-specific optogenetic mechanostimulator named LIMER. Mechanostimulation of ER by using LIMER can induce Ca2+ release from ER, inhibit ER-to-Golgi trafficking, and increase levels of ER stress markers—providing direct proof for the mechanosensitivity of ER and the mechanoregulation of ER functions.
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