N‐glycan processing selects ERAD‐resistant misfolded proteins for ER‐to‐lysosome‐associated degradation

Fregno, Ilaria; Fasana, Elisa; Soldà, Tatiana; Galli, Carmela; Molinari, Maurizio

doi:10.15252/embj.2020107240

Cited by 38 publications

(64 citation statements)

References 89 publications

(287 reference statements)

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“…Cytosolic accumulation and aggregation of misfolded proteins upon defective clearance are involved in conditions such as spongiform neurodegeneration and severe ataxia. Misfolded proteins in the ER are translocated to the cytosol for proteasomal degradation via ER-associated degradation (ERAD) [11]. Proteins which do not engage ERAD factors are segregated in ER subdomains and delivered to endolysosomes for ER-to-lysosome-associated degradation (ERLAD) under the control of ER-phagy receptors [12,13].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Pinto

Ninfole

Benedetti

et al. 2021

Cells

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Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

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Section: Introductionmentioning

confidence: 99%

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Pinto

Ninfole

Benedetti

et al. 2021

Cells

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“…These receptors accumulate, leading to membrane deformation. The subsequent targeting of the ER for degradation often occurs through recruitment of ATG8/LC-3 proteins located on autophagic membranes, followed by engulfment and trafficking of ER membrane to the lysosome (Sun and Brodsky, 2019;Grumati et al, 2018;Fumagalli et al, 2016;Omari et al, 2018;Loi et al, 2019;Fregno et al, 2021). The mechanisms regulating engulfment/scission are unknown.…”

Section: Er-to-lysosomal Associated Degradative (Erlad)mentioning

confidence: 99%

“…Micro-ER-phagy and LC3/Atg8-dependent vesicular delivery described processes where the ER is directly targeted to the lysosome without autophagic engulfment (Fregno and Molinari, 2019). Micro-ER-phagy has been observed during recovery from ER stress, and in response to aggregation of misfolded proteins in the ER that are resistant to ERAD, such as in AATD or procollagen I which will be discussed later in this review (Fregno and Molinari, 2018;Fregno et al, 2021). In mammals, the micro-ER-phagy and LC3-Atg8-dependent vesicular delivery pathways currently identified involve LC-3 lipidation, which targets the ER to interact with endolysosomal membranes followed by fusion of the membranes and degradation of the target proteins (Molinari, 2021).…”

Section: Er-to-lysosomal Associated Degradative (Erlad)mentioning

confidence: 99%

“…In mammals, the micro-ER-phagy and LC3-Atg8-dependent vesicular delivery pathways currently identified involve LC-3 lipidation, which targets the ER to interact with endolysosomal membranes followed by fusion of the membranes and degradation of the target proteins (Molinari, 2021). This process was found to degrade protein aggregates through a non-rapamycin responsive mechanism, suggesting that the autophagosome is not involved (Fregno and Molinari, 2018;Fregno et al, 2021). FAM134B was found to play a role not only in macro-ER-phagy, but also LC3/Atg8dependent vesicular delivery.…”

Section: Er-to-lysosomal Associated Degradative (Erlad)mentioning

confidence: 99%

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ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Duwaerts

Maiers

2022

Front. Mol. Biosci.

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The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.

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“…Eventually, vesicles containing aggregates are fused with endolysosomes to be degraded [ 15 ]. Furthermore, a recent study showed that glucose processing of N-glycans of proteasome-resistant misfolded proteins, such as ATZ, is required for targeting these proteins for degradation by ERLAD [ 24 ]. In this process, CALNEXIN works with UDP-glucose: glycoprotein glucosyltransferase (UGGT1) and other glucose processing enzymes to mediate substrates selection [ 24 ].…”

Section: Er-phagymentioning

confidence: 99%

Advances in ER-Phagy and Its Diseases Relevance

Qian

Cui

2021

Cells

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As an important form of selective autophagy in cells, ER-phagy (endoplasmic reticulum-selective autophagy), the autophagic degradation of endoplasmic reticulum (ER), degrades ER membranes and proteins to maintain cellular homeostasis. The relationship between ER-phagy and human diseases, including neurodegenerative disorders, cancer, and other metabolic diseases has been unveiled by extensive research in recent years. Starting with the catabolic process of ER-phagy and key mediators in this pathway, this paper reviews the advances in the mechanism of ER-phagy and its diseases relevance. We hope to provide some enlightenment for further study on ER-phagy and the development of novel therapeutic strategies for related diseases.

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N‐glycan processing selects ERAD‐resistant misfolded proteins for ER‐to‐lysosome‐associated degradation

Cited by 38 publications

References 89 publications

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases

ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets

Advances in ER-Phagy and Its Diseases Relevance

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