Advances in ER-Phagy and Its Diseases Relevance

He, Lingang; Qian, Xuehong; Cui, Yixian

doi:10.3390/cells10092328

Cited by 14 publications

(11 citation statements)

References 142 publications

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“…However, the involvement of ERLAD in the controlled degradation of selected protein regulators of metabolic pathways is likely, and its pharmacologic modulation to alleviate disease phenotypes is only a matter of time. In fact, ERLAD clients are associated with several rare genetic diseases (Table 1, [7,82,89,[105][106][107][108][109][110][111][112][113][114][115][116][117][118][119]), most of which have no effective cure to date. It is conceivable that pharmacologic or genetic inhibition of ERLAD may alleviate disorders caused by mutations that delay polypeptide folding and allow the clearance machinery to kick in before the native, transport-competent structure is eventually attained [120].…”

Section: Discussionmentioning

confidence: 99%

ER‐to‐lysosome‐associated degradation in a nutshell: mammalian, yeast, and plant ER‐phagy as induced by misfolded proteins

Rudinskiy

Molinari

2023

FEBS Letters

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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.

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Section: Discussionmentioning

confidence: 99%

ER‐to‐lysosome‐associated degradation in a nutshell: mammalian, yeast, and plant ER‐phagy as induced by misfolded proteins

Rudinskiy

Molinari

2023

FEBS Letters

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“…ER-phagy is thought to be a highly orchestrated process that is regulated by specific ER receptors unique to the type of ER network (ie, ER sheets versus ER tubuli). 46 This is especially intriguing in cardiac myocytes, given the presence of both ER and sarcoendoplasmic reticulum. As it relates to ERAD, a form of micro-er-phagy has been described in yeast whereby select proteins as opposed to whole ER fragments are degraded using these same ER-phagy receptors, which implicates ER-phagy as a preferred adaptive degradation mechanism if ERAD is impaired.…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Form of ERAD Regulates Cardiac Hypertrophy

et al. 2023

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BACKGROUND: Cardiac hypertrophy increases demands on protein folding, which causes an accumulation of misfolded proteins in the endoplasmic reticulum (ER). These misfolded proteins can be removed by the adaptive retrotranslocation, polyubiquitylation, and a proteasome-mediated degradation process, ER-associated degradation (ERAD), which, as a biological process and rate, has not been studied in vivo. To investigate a role for ERAD in a pathophysiological model, we examined the function of the functional initiator of ERAD, valosin-containing protein–interacting membrane protein (VIMP), positing that VIMP would be adaptive in pathological cardiac hypertrophy in mice. METHODS: We developed a new method involving cardiac myocyte-specific adeno-associated virus serovar 9–mediated expression of the canonical ERAD substrate, TCRα, to measure the rate of ERAD, ie, ERAD flux, in the heart in vivo. Adeno-associated virus serovar 9 was also used to either knock down or overexpress VIMP in the heart. Then mice were subjected to transverse aortic constriction to induce pressure overload–induced cardiac hypertrophy. RESULTS: ERAD flux was slowed in both human heart failure and mice after transverse aortic constriction. Surprisingly, although VIMP adaptively contributes to ERAD in model cell lines, in the heart, VIMP knockdown increased ERAD and ameliorated transverse aortic constriction–induced cardiac hypertrophy. Coordinately, VIMP overexpression exacerbated cardiac hypertrophy, which was dependent on VIMP engaging in ERAD. Mechanistically, we found that the cytosolic protein kinase SGK1 (serum/glucocorticoid regulated kinase 1) is a major driver of pathological cardiac hypertrophy in mice subjected to transverse aortic constriction, and that VIMP knockdown decreased the levels of SGK1, which subsequently decreased cardiac pathology. We went on to show that although it is not an ER protein, and resides outside of the ER, SGK1 is degraded by ERAD in a noncanonical process we call ERAD-Out. Despite never having been in the ER, SGK1 is recognized as an ERAD substrate by the ERAD component DERLIN1, and uniquely in cardiac myocytes, VIMP displaces DERLIN1 from initiating ERAD, which decreased SGK1 degradation and promoted cardiac hypertrophy. CONCLUSIONS: ERAD-Out is a new preferentially favored noncanonical form of ERAD that mediates the degradation of SGK1 in cardiac myocytes, and in so doing is therefore an important determinant of how the heart responds to pathological stimuli, such as pressure overload.

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“…Several classic ER-phagy substrates are misfolded, mutant proteins associated with a range of metabolic diseases [51,84]. Studying these molecules-including mutant proinsulin, procollagen, and ATZ-has illuminated our understanding not just of metabolic disease, but also of basic ER biology [85].…”

Section: Metabolic Disordersmentioning

confidence: 99%

Autophagy of the ER: the secretome finds the lysosome

Knupp,

Pletan,

Arvan

et al. 2023

The FEBS Journal

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Lysosomal degradation of the endoplasmic reticulum (ER) and its components through the autophagy pathway has emerged as a major regulator of ER proteostasis. Commonly referred to as ER‐phagy and ER‐to‐lysosome‐associated degradation (ERLAD), how the ER is targeted to the lysosome has been recently clarified by a growing number of studies. Here, we summarize the discoveries of the molecular components required for lysosomal degradation of the ER and their proposed mechanisms of action. Additionally, we discuss how cells employ these machineries to create the different routes of ER‐lysosome‐associated degradation. Further, we review the role of ER‐phagy in viral infection pathways, as well as the implication of ER‐phagy in human disease. In sum, we provide a comprehensive overview of the current field of ER‐phagy.

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Advances in ER-Phagy and Its Diseases Relevance

Cited by 14 publications

References 142 publications

ER‐to‐lysosome‐associated degradation in a nutshell: mammalian, yeast, and plant ER‐phagy as induced by misfolded proteins

ER‐to‐lysosome‐associated degradation in a nutshell: mammalian, yeast, and plant ER‐phagy as induced by misfolded proteins

Noncanonical Form of ERAD Regulates Cardiac Hypertrophy

Autophagy of the ER: the secretome finds the lysosome

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