Autophagy: an ER Protein Quality Control Process

Kruse, Kristina B.; Brodsky, Jeffrey L.; McCracken, Ardythe A.

doi:10.4161/auto.2.2.2388

Cited by 93 publications

(76 citation statements)

References 17 publications

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“…It is therefore unclear if autophagy degrades heterologously expressed mutant ␣ 1 -antitrypsin in fibroblasts to a greater or lesser extent compared with WT ␣ 1 -antitrypsin. Further studies in yeast identified Z ␣ 1 -antirypsin degradation-deficient (add) mutants, of which one (add3) could be complemented by VPS30/Atg6, a component of a PI 3-kinase complex involved in autophagy (39). Thus it was suggested that separate pathways might be responsible for degrading soluble Z ␣ 1 -antitrypsin and large aggregates.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins

Kroeger

Miranda

Ian

et al. 2009

Journal of Biological Chemistry

133

150

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The serpinopathies are a family of diseases characterized by the accumulation of ordered polymers of mutant protein within the endoplasmic reticulum. They are a diverse group including ␣ 1 -antitrypsin deficiency and the inherited dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. We have used transient transfection of COS7 cells and mouse embryonic fibroblasts, PC12 cell lines that conditionally express wild type and mutant neuroserpin and fly models of FENIB to assess the cellular handling of wild type and mutant serpins. By using a polymer-specific monoclonal antibody, we show that mutant neuroserpin forms polymers after a delay of at least 30 min and that polymers can be cleared in PC12 cell lines and from the brain in a fly model of FENIB. At steady state, the fractions of intracellular polymerogenic G392E mutant neuroserpin in the monomeric and polymeric states are comparable. Inhibition of the proteasome with MG132 reveals that both mutant neuroserpin and ␣ 1 -antitrypsin are degraded predominantly by endoplasmic reticulum-associated degradation (ERAD). Pharmacological and genetic inhibitions demonstrate that autophagy is responsible for bulk turnover of wild type and mutant serpins, but can be stimulated by rapamycin to compensate for proteasome inhibition. The significance of these findings to the treatment of serpinopathies is discussed.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins

Kroeger

Miranda

Ian

et al. 2009

Journal of Biological Chemistry

133

150

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“…This Tg-dependent loss in total FT ALLC cannot be reversed using proteasome inhibitors (bortezomib or MG132) or the p97 inhibitor eeyarestatin I [a potent inhibitor of ER-associated degradation (ERAD) (35)], indicating that FT ALLC is degraded following ER stress, at least in part through an ERAD-independent mechanism (Fig. 2E) (36). In contrast, the autophagy inhibitor chloroquine stabilized ALLC against Tg-induced degradation, indicating that Tg increases the autophagic degradation of ALLC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain

Cooley¹,

Ryno²,

Plate³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

128

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Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼70% of patients who do not exhibit significant organ proteotoxicity and can tolerate chemotherapy. Thus, identifying new therapeutic strategies to alleviate LC organ proteotoxicity should allow AL patients with significant cardiac and/or renal involvement to subsequently tolerate established chemotherapy treatments. Using a small-molecule screening approach, the unfolded protein response (UPR) was identified as a cellular signaling pathway whose activation selectively attenuates secretion of amyloidogenic LC, while not affecting secretion of a nonamyloidogenic LC. Activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the absence of stress recapitulates the selective decrease in amyloidogenic LC secretion by remodeling the endoplasmic reticulum proteostasis network. Stress-independent activation of XBP1s, or especially ATF6, also attenuates extracellular aggregation of amyloidogenic LC into soluble aggregates. Collectively, our results show that stress-independent activation of these adaptive UPR transcription factors offers a therapeutic strategy to reduce proteotoxicity associated with LC aggregation.ER proteostasis | amyloid L ight-chain amyloidosis (AL) afflicts 8-10 people per million per year, making it the most prominent systemic amyloid disease (1). AL is a gain-of-toxic function disease driven by a clonally expanded plasma cell that secretes amyloidogenic Ig light chains (LCs). These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that interact with distal tissues such as the kidney, heart, and gastrointestinal tract, leading to organ dysfunction and ultimately death by unknown proteotoxicity mechanism(s) (2).The majority of AL patients must combat both a cancer (i.e., the clonally expanded plasma cell) and LC aggregation-associated proteotoxicity. The standard treatment for AL patients is chemotherapy (often combined with stem cell transplant) to eliminate the cancerous plasma cell population (3, 4). The proteasome inhibitor bortezomib, which takes advantage of the stress sensitivity of aggressively proliferating plasma cells, has transformed chemotherapy effectiveness (5-7). Regardless, ∼30% of AL patients with substantial cardiac or renal LC proteotoxicity are too ill at diagnosis to tolerate chemotherapeutics (8-10). Thus, new strategies to reduce LC organ proteotoxicity must be developed to allow more AL patients to take advantage of chemotherapy.LC aggregation requires conformational changes and a sufficient concentration of misfolded LC in plasma, which determine the rate and extent of its concentration-dependent aggregation. Over 500 distinct LC s...

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“…Indeed, autophagy is thought to be a part of the ER stress response probably as an alternate to ER-associated protein degradation (ERAD) if the latter is overloaded. 35 Autophagy is thought to alleviate ER stress and inhibit apoptosis, by mediating, in part, the removal of ER-accumulated protein, via the ER-associated chaperone GRP78/BiP, and the release of Ca 2 þ from the ER into the cytosol. However, in case of prolonged ER stress, the protective effect of autophagy may switch to cell death.…”

Section: Discussionmentioning

confidence: 99%

HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs

et al. 2010

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The apoptotic effect of oxidized LDLs (oxLDLs) is mediated through a complex sequence of signaling events involving a deregulation of the cytosolic Ca 2 þ homeostasis. OxLDLs also trigger ER stress that may lead to cellular dysfunction and apoptosis, through the activation of the IRE1a/c-Jun N-terminal kinase pathway. Moreover, ER stress and oxidized lipids have been shown to trigger autophagy. The antiatherogenic high-density lipoproteins (HDLs) display protective effects against oxLDLs toxicity. To more deeply investigate the mechanisms mediating the protective effects of HDLs, we examined whether ER stress and autophagy were implicated in oxLDLs-induced apoptosis and whether HDLs prevented these stress processes. We report that, in human endothelial cells, HDLs prevent the oxLDL-induced activation of the ER stress sensors IRE1a, eIF2a and ATF6 and subsequent activation of the proapoptotic mediators JNK and CHOP. OxLDLs also trigger the activation of autophagy, as assessed by LC3 processing and Beclin-1 expression. The autophagic process is independent of the proapoptotic arms of ER stress, but Beclin-1 contributes to PS exposure and subsequent phagocytosis of oxLDLs exposed cells. Induction of autophagy and PS exposure by oxLDLs is prevented by HDLs. Finally, the cytosolic Ca 2 þ deregulation triggered by oxLDLs is a common signaling pathway that mediates ER stress-induced cell death and autophagy, all these events being blocked by HDLs.

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Autophagy: an ER Protein Quality Control Process

Abstract: Previously published online as an Autophagy E-publication:

Cited by 93 publications

References 17 publications

Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins

Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins

Unfolded protein response activation reduces secretion and extracellular aggregation of amyloidogenic immunoglobulin light chain

HDLs inhibit endoplasmic reticulum stress and autophagic response induced by oxidized LDLs

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