Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome

Ding, Wen; Yin, Xiao Ming

doi:10.4161/auto.5190

Cited by 337 publications

(282 citation statements)

References 94 publications

(221 reference statements)

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“…In the present study, we therefore aimed at identifying the molecular basis of this inducible escape mechanism. ST80/Bortezomib cotreatment triggers accumulation of insoluble protein aggregates As inhibition of the proteasome or HDAC6 has previously been shown to cause accumulation of ubiquitin-positive, insoluble protein aggregates, 16,17 we analyzed protein aggregates upon treatment with ST80 and/or Bortezomib by fractioning cell lysates in TritonX-100 soluble and insoluble fractions. Of note, we detected a marked increase of ubiquitinated protein aggregates in the insoluble fraction in cells cotreated with ST80/Bortezomib (Figure 2a).…”

Section: Resultsmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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Simultaneous inhibition of the two major constitutive protein quality control (PQC) pathways, that is, the ubiquitin-proteasome system (UPS) and the aggresome-autophagy system, has been suggested as a promising strategy to trigger cell death in cancer cells. However, we observed that one third of rhabdomyosarcoma (RMS) cells survives parallel inhibition of the UPS by Bortezomib and the aggresome-autophagy pathway by the cytoplasmic histone deacetylase 6 inhibitor ST80, and is able to regrow upon drug removal, thus pointing to the induction of compensatory pathways. Here, we identify Bcl-2-associated athanogene 3 (BAG3) as a critical mediator of inducible resistance in surviving cells after concomitant blockage of constitutive PQC pathways by mitigating ST80/Bortezomib-triggered proteotoxicity via selective autophagy. ST80/Bortezomib cotreatment upregulates BAG3 mRNA and protein levels in surviving cells in addition to triggering the accumulation of insoluble protein aggregates. Intriguingly, knockdown of BAG3 by RNA interference severely impairs clearance of protein aggregates, significantly increases cell death and reduces longterm survival and clonogenic growth during recovery after ST80/Bortezomib cotreatment. Similarly, inhibition of autophagy by inducible autophagy-related protein 7 knockdown prevents removal of protein aggregates and cell regrowth during recovery after ST80/Bortezomib cotreatment. Also, the inhibition of lysosomal degradation using the V-ATPase pump inhibitor Bafilomycin A1 enhances accumulation of protein aggregates, and completely abolishes regrowth after Bortezomib/ST80-induced proteotoxic stress. By identifying BAG3 as a key mediator of inducible resistance by mitigating proteotoxicity via selective autophagy after inhibition of constitutive PQC systems, our study provides new insights into the regulation of PQC pathways in cancer cells and identifies new targets for therapeutic intervention.

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Section: Resultsmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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“…71 In addition to these specific shared substrates, misfolded proteins are common substrates for both the UPS and autophagy. 29,72 Whether this relates to Dronc, is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

et al. 2016

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A major function of ubiquitylation is to deliver target proteins to the proteasome for degradation. In the apoptotic pathway in Drosophila, the inhibitor of apoptosis protein 1 (Diap1) regulates the activity of the initiator caspase Dronc (death regulator Nedd2-like caspase; caspase-9 ortholog) by ubiquitylation, supposedly targeting Dronc for degradation by the proteasome. Using a genetic approach, we show that Dronc protein fails to accumulate in epithelial cells with impaired proteasome function suggesting that it is not degraded by the proteasome, contrary to the expectation. Similarly, decreased autophagy, an alternative catabolic pathway, does not result in increased Dronc protein levels. However, combined impairment of the proteasome and autophagy triggers accumulation of Dronc protein levels suggesting that autophagy compensates for the loss of the proteasome with respect to Dronc turnover. Consistently, we show that loss of the proteasome enhances endogenous autophagy in epithelial cells. We propose that enhanced autophagy degrades Dronc if proteasome function is impaired.

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“…61 How the misfolded proteins are recognized and removed by the autophagosome is not fully understood. 55 The unfolded protein response (UPR) pathway can be involved. Using generic ER stress inducers, such as A23187 and thapsigargin, and proteasome inhibitors, which cause the accumulation of misfolded polyubiquitinated proteins and ER stress, we and others found that the IRE1-JNK pathway is important for autophagy induction.…”

Section: Role Of Autophagy In Clearing Misfolded Proteins In Liver DImentioning

confidence: 99%

“…However, some clues might be derived from the understanding of autophagic degradation of misfolded proteins under pathological conditions. 55 Alpha-1-Antitrypsin Deficiency and Hypofibrinogenemia. Alpha-1-antitrypsin (AT), the archetype of the Serpin supergene family, is the principal blood-borne inhibitor of destructive neutrophil proteases.…”

Section: Role Of Autophagy In Clearing Misfolded Proteins In Liver DImentioning

confidence: 99%

Autophagy in the liver

2008

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A great part of our current understanding of mammalian macroautophagy is derived from studies of the liver. The term "autophagy" was introduced by Christian de Duve in part based on ultrastructural changes in rat liver following glucagon injection. Subsequent morphological, biochemical, and kinetics studies of autophagy in the liver defined the basic process of autophagosome formation, maturation, and degradation and the regulation of autophagy by hormones, phosphoinositide 3-kinases, and mammalian target of rapamycin. It is now clear that macroautophagy in the liver is important for the balance of energy and nutrients for basic cell functions, the removal of misfolded proteins resulting from genetic mutations or pathophysiological stimulations, and the turnover of major subcellular organelles such as mitochondria, endoplasmic reticulum, and peroxisomes under both normal and pathophysiological conditions. Disturbance of autophagy function in the liver could thus have a major impact on liver physiology and liver disease. (HEPATOLOGY 2008;47: 1773-1785.)

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Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome

Cited by 337 publications

References 94 publications

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila

Autophagy in the liver

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