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Autophagy and ER stress

Autophagy and ER stress

Li, W. Alteration of autophagosomal Autophaty LC3, GABARAP and GATE in Lewy body disease. Hotamisligil GS.


Autophagy from Fundamental Mechanisms to Mechanical Stress in Physiology and Disease

Autophagy and ER stress -

Crosstalk between ER stress, autophagy and inflammation. The arms of UPR activating inflammation also intersect with pathways regulating autophagy.

The possible points of intersection are shown in the illustration. Intestinal epithelial cells IECs are constantly exposed to microbiota, metabolites and toxins which force them to produce large amounts of cytokines and various other proteins resulting in ER-stress.

Although, UPR helps in resolving ER-stress, continued ER-stress and disruptions in the UPR mechanism can result in chronic inflammation.

Therefore, it is no surprise that studies have associated UPR dysregulation with Crohn's disease CD and ulcerativecolitis UC , two major types of IBDs 47 , IBD is also one of the first polygenic disease to be genetically linked to UPR components Intestinal inflammation is primarily linked to IRE1-XBP1 arm of the UPR pathway because mice deleted of the IRE1 gene in mouse intestinal epithelium are more susceptible to dextran sulfate sodium DSS -induced colitis Similarly, mice deficient in XBP-1 in the intestine develop spontaneous intestinal inflammation and immune infiltration resembling IBD The barrier between microbial flora of the gut and IECs is maintained by the secretion of mucin2 MUC2.

UPR and intestinal inflammation has been also linked in humans. For instance, anterior gradient 2 AGR2 encoding a protein-disulfide-isomerase which enables protein folding and orosomucoid-like 3 ORMDL3 , which regulates ER calcium have been shown to induce UPR 53 — Furthermore, genome-wide association studies GWAS have mapped the XBP-1 gene locus as an IBD susceptibility region 57 , As described before, UPR interacts with autophagy pathways at multiple levels.

UPR induces autophagy and reciprocally, autophagy may limit UPR by reducing ER-stress Interestingly, a core autophagy effector protein ATG16L is associated with IBD in humans.

Consistently, mice deficient in ATG16L1 in IECs develop Crohn's like disease 60 — Furthermore, deletion of ATG16L1 and XBP1 in IECs results in more severe IBD suggesting that autophagy and UPR synergizes in regulating intestinal inflammation UPR is also associated with the pathogenesis of chronic obstructive pulmonary disease COPD.

External stimulants such as cigarette smoke induces ROS production which disturbs the redox environment thus preventing proper protein folding by modulating the protein-disulfide-isomerase PDI Dysregulation of protein folding in lung and bronchial epithelial cells induces UPR 64 , Furthermore, oxidative damage of proteins caused by cigarette smoke leads to impaired degradation of misfolded, non-functional proteins triggering UPR Cigarette smoke induced-UPR is characterized by PERK-eIF2a-mediated CHOP induction 64 , 66 — Impaired autophagy has been linked to cigarette smoke induced inflammation.

On the contrary, activating autophagy using mTOR inhibitor rapamycin results in increased apoptosis and inflammation Interestingly, another form of autophagy known as chaperone-mediated autophagy CMA , which is LAMP2A facilitated selective degradation of proteins containing Lys-Phe-Gln-Arg-Gln KFERQ in the lysosomes mitigates cigarette smoke induced UPR and apoptosis MS is an autoimmune disorder in which the T-cells target myelin sheath ER-stress induced UPR is found to be a hallmark of MS It is proposed that autophagy-induced cell death could be a possible mechanism by which UPR resolves ER-stress.

Hence, autophagy is elevated in MS-lesions resulting in demyelination and neuro-inflammation. PERK and CHOP activation has been found to be consistent with upregulation of BAX and BCL2 in experimental autoimmune encephalomyelitis EAE. However, the molecular mechanisms integrating UPR, autophagy and inflammation has not been completely understood 3.

Parkinson's Disease PD is a neurodegenerative disease and numerous evidences suggest that inflammation exacerbates the disease Reports have also linked the role of ER-stress in the pathogenesis of PD using neurotoxic models of PD. Interestingly, depletion of CHOP protects dopaminergic neurons against hydroxydopamine 6-OHDA indicating the involvement of ER-stress in PD Similarly, silencing XBP1 another UPR arm results in chronic ER stress and dopaminergic neuron degeneration Parkin an E3 ubiquitin ligase implicated in Parkinson's disease is a key regulator of mitochondria-specific autophagy mitophagy.

Interestingly, ATF4 upregulates parkin by directly binding to the promoter region upon ER stress Although, studies addressing the cross talk between ER stress, autophagy and inflammation in PD are limited, UPR can co-regulate inflammation and autophagy as discussed above.

Intriguingly, ER stress that is implicated in inflammation and autophagy has been currently coupled with the pathophysiological aspects of the cardiovascular system CVS Upregulation of UPR is observed in cardiac hypertrophy and heart failure.

Inflammation and ER stress within the CVS are connected through various regulators such as NF-κB, JNK, spliced XBP-1 and ROS 80 — As discussed in earlier sections of this review, UPR activation leads to recruitment of TRAF2 by IRE1 which interacts with JNK and IκB resulting in the activation of downstream inflammatory signaling and cytokine production.

Additionally, IRE1 auto-phosphorylates and splices its downstream XBP-1 which stimulates the production of inflammatory cytokines by enhancing Toll-like receptor TLR signaling 32 , ATF6 activation also results in transcriptional activation of inflammatory proteins like C-reactive protein CRP which fosters the expression of monocyte chemoattractant protein-1 MCP-1 and contributes to inflammation 84 , Furthermore, ATF6 phosphorylates AKT and activates NF-κB which stimulates the expression of various cytokines Similarly, PERK also triggers NF-κB-induced cytokine signaling by activating IκB It is well-established that ER stress is also implicated in atherosclerosis where UPR activation is observed in macrophage-derived and smooth muscle cell SMC -derived foam cells 79 , The plaque deposition in the arterial walls triggers infiltration of macrophages and neutrophils leading to production of IL-1 and IL-6 Additionally, ROS is induced resulting in UPR activation which can further enhance inflammation and tissue damage Inflammation induced mitochondrial damage and ROS can in turn induce autophagy A weak association between autophagy and plaque formation has been reported based on the expression of autophagy markers 91 , However, whether autophagy is beneficial or detrimental in atherosclerosis is poorly understood.

Traditionally, engagement of PRRs with PAMPs has been considered the primary trigger for inflammation. However, changes in intracellular functions causing cellular stress have been lately recognized to play a key role in inflammation associated with pathologies.

Thus, ER stress-induced inflammation has been implicated in several inflammatory diseases. Although response to ER-stress UPR aids in mitigating ER-stress, UPR pathways also promote inflammation and diseases such as diabetes, obesity, IBD, inflammatory lung disorders, cardiovascular diseases and cancer.

Moreover, UPR pathways are interlinked with other cellular-stress response mechanisms such as autophagy which can potentially mitigate inflammation and disease progression.

Conversely, activation of cellular homeostasis mechanisms such as autophagy can be an impediment to treat diseases such as cancer. However, UPR induced inflammation and autophagy vary between diseases and is cell type dependent.

Although, inflammation and autophagy have been reported during ER-stress, it is correlative. Therefore, molecular mechanisms that integrate UPR, autophagy and inflammation need to be elucidated which is crucial for therapeutic targeting.

SC: prepared the manuscript draft and figures. All authors contributed to the article and approved the submitted version. Research in the laboratory of NR was supported by funds from the Center for Cancer Biology, University of South Australia and Neurosurgical Research Foundation, Adelaide, Australia.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Hotamisligil GS. Inflammation and metabolic disorders. doi: PubMed Abstract CrossRef Full Text Google Scholar.

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RAB1 overexpression protects DA neurodegeneration in various PD animal models Cooper et al. Additionally, α-SYN binds to high mobility group box 1 HMGB1 and strengthens BECLIN-BCL2 binding by blocking HMGB1-BECLIN1 interaction Song et al. Both wild-type and A53T α-SYN can induce mTOR activity and impair autophagy Jiang et al.

In an AAV-mediated α-SYN overexpression mouse model, α-SYN impairs autophagic efflux by sequestering TFEB in the cytoplasm, accompanied by p62 and LC3-II accumulation Decressac et al. Similarly, PC12 cells harboring A53T α-SYN display accumulated autophagic-vesicular structures and impaired lysosomal hydrolysis Stefanis et al.

Interestingly, wild-type α-SYN contains a KFERQ sequence and is greatly degraded through the CMA pathway, while pathogenic α-SYN mutants act as CMA uptake inhibitors through interacting with LAMP2A on the lysosomal membrane Cuervo et al.

AAV-mediated overexpression of A53T α-SYN in neurons or A53T α-SYN in transgenic mice results in a reduction of CMA-mediated proteolysis of other substrates Xilouri et al.

Interestingly, modification of wild-type α-SYN by DA also impairs CMA proteolysis, similar to mutant α-SYN Martinez-Vicente et al. Whether wild-type and pathogenic α-SYN have an effect on phosphorylation and the activity of LAMP2A is not clear.

Mutations in Parkin Kitada et al. Parkin is an E3 ligase and functions in the ERAD of misfolded ER proteins Shimura et al. Parkin is upregulated by ATF4 under either ER stress or mitochondrial stress and inhibits stress-induced mitochondrial dysfunction and cell death via its E3 ligase activity Imai et al.

Conversely, an accumulation of PAEL receptor, a substrate of Parkin, induces ER stress and cell death Imai et al. Furthermore, the ER stress inhibitor salubrinal prevents rotenone-induced ER stress and cell death through the ATF4-Parkin pathway Wu et al. Parkin also regulates ER stress and UPR via transcription factor pdependent XBP1 transcription regulation Duplan et al.

It has been reported that Parkin participates in ER stress regulation in DA neurons and also in astrocytes Ledesma et al. Moreover, an activation of the PERK branch of the UPR was observed that was induced by defective mitochondria, and PERK inhibition is neuroprotective in parkin mutant flies Celardo et al.

It has been shown that PINK1 inhibits ER stress-induced damage to mouse primary cortical neurons Li and Hu, , and downregulation of ER stress response genes has been detected in aged Pink1 knockout mice Torres-Odio et al. Parkin and PINK1 are two important regulators that control mitophagy and mitochondrial homeostasis Swerdlow and Wilkins, Mitophagy, the process of removing damaged mitochondria, is compromised in PD pathogenesis, and its dysfunction is closely associated with DA neurodegeneration Liu et al.

It has been reported that the ER stress induced by tunicamycin TM and thapsigargin TG prevents Parkin loss and promotes its recruitment to the mitochondria, and also activates mitophagy during reperfusion after ischemia Zhang et al.

However, the crosslink and mechanisms between ER stress and mitophagy in PD pathogenesis are mainly unknown. LRRK2 possesses kinase function for catalyzing substrates and GTPase function for GTP-GDP hydrolysis. LRRK2 is co-localized with ER markers in DA neurons Vitte et al.

LRRK2 phosphorylates leucyl-tRNA synthetase LRS , and this increases the number of misfolded proteins, causes ER stress, and induces autophagy initiation Ho et al.

LRRK2-GS mutation exacerbates these processes. It has recently been reported that LRRK2 regulates ER-mitochondria tethering through the PERK-mediated activation of E3 ligases, and LRKK2 mutation enhances the sensitivity to ER stress and decreases mitochondrial biogenesis Toyofuku et al.

It has been reported that LRRK2 functions in endosomal- and vesicle-trafficking pathways, plays roles in cytoskeleton dynamics and neurite outgrowth, and regulates multiple steps of the autophagy-lysosome pathway Madureira et al. Although wild-type and mutant LRRK2 promote autophagy by ER stress induced by the phosphorylation of LRS, they impair the autophagic degradation in an LRS-independent manner Ho et al.

LRKK2-GS fibroblasts exhibit higher autophagic activity levels involved in activating ERK activity rather than the mTOR pathway Bravo-San Pedro et al. LRRK2 and LRRK2-GS also regulate p62 phosphorylation, influence its affinity to ubiquitinated cargo Park et al. Additionally, LRKK2 and LRKK2-GS inhibit autophagosome formation and autophagosome-lysosome fusion in various LRRK2-related PD models may through regulating phosphorylation of a number of RAB proteins Madureira et al.

LRKK2 pathogenic mutants also impair lysosomal function, which is detected by abnormal lysosomal morphology, abnormal cellular lysosomal localization, increased lysosomal pH, or inhibition of lysosomal enzymes Madureira et al.

Like α-SYN, LRKK2 can also be degraded by CMA, and unlike α-SYN mutants, which increase the binding affinity of HSC70 and LAMP2A, LRRK2 mutants block the formation of the CMA translocation complex by inducing LAMP2A and HSC70 accumulation at the lysosomal membrane Orenstein et al.

Together, the promotion of autophagy initiation by LRRK2 and its pathogenic mutants is partly due to ER stress and UPR activation. However, they most likely inhibit autophagic flux, as well as CMA and lysosomal functions in an ER stress-independent manner. DJ-1, a protein encoded by the PARK7 gene, assumes multiple functions including antioxidative stress and chaperone properties Mencke et al.

Mutations or deletions of DJ-1 are associated with autosomal-recessive early-onset forms of PD Bonifati et al. DJ-1 regulates ER stress and UPR by binding to and stabilizing ATF4 mRNA under both basal and stress conditions Yang et al. DJ-1 can also protect against ER stress-induced cell death in Neuro2a cells Yokota et al.

Moreover, it has been shown that oxidized DJ-1 can interact with N-terminal arginylated GPR78, and thus facilitate the self-polymerization of p62 and the targeting of pcargo complexes to phagophores under oxidative stress Lee et al.

Interestingly, DJ-1 expression is regulated under ER stress such that XBP1 directly binds to its promoter and stimulates its expression Duplan et al. Overexpression of DJ-1 in DA neurons and in the SN of rat brains promotes ERK-dependent autophagy.

Although there are no obvious effects of DJ-1 deficiency on autophagy in SH-SY5Y cells Gonzalez-Polo et al. In addition, DJ-1 deficiency in microglia impairs autophagy-mediated p62 degradation and reduces microglial-mediated α-SYN phagocytosis Nash et al.

DJ-1 protects against DA neurodegeneration through enhancing CMA in PD animal models, SH-SY5Y cells, and astrocytes Xu et al. Together, the upregulation of DJ-1 expression in response to ER stress may enhance the CMA or autophagic degradation of aggregated proteins, which bridges the close link between ER stress and autophagy in PD pathogenesis.

MPTP is the best-known chemical for inducing a PD model in vivo. Intraperitoneally injecting mice with MPTP reproduces PD pathology, including the selective loss of DA neurons in the SN and accumulation of protein aggregates, and eventually leads to the onset of PD-like clinical symptoms Bove et al.

MPTP also promotes the phosphorylation of p38 and enhances the interaction between phosphorylated p38 and ATF6, leading to an increase in ATF6 transcriptional activity Egawa et al.

Increased levels of GRP78 and CHOP expression, as well as phosphorylated PERK and eIF2α, are detected in DA cellular models that are subjected to 6-OHDA treatment Ryu et al. A recent study indicated that 6-OHDA treatment induces excessive autophagy with increased AMPK activity, decreased mTOR activity, reduced p62 levels, and also prevents alterations in lysosomal functions Chung et al.

In addition, 6-OHDA treatment stimulates CMA activity by increasing LAMP2A levels Wang et al. Together, 6-OHDA-induced excessive autophagy activation and autophagic flux contribute to PD pathogenesis. Rotenone treatment produces most of the movement disorder symptoms and the histopathological features of PD, including LBs Betarbet et al.

Rotenone also triggers ATF4 and CHOP expression involving activation of IRE1α and PERK in cellular models Ryu et al. An induction of the IRE1α and PERK branch of the UPR has also been shown in rotenone rat or mouse models of PD Tong et al.

Treatment of N2a cells with rotenone triggers ER stress and the UPR involving all three branches of PERK, IRE1α, and ATF6 Gupta et al. Rotenone induces an increase in autophagy related proteins LC3-II and BECLIN1, as well as in autophagy substrates such as α-SYN and p62 in cultured PC12 cells Wu et al.

Rotenone increases oligomeric wild-type and A53T α-SYN in transfected cells through inhibiting their autophagic degradation Yu et al. Therefore, rotenone-induced ER stress and the UPR initiate autophagy induction but block autophagic flux by impairing lysosomal functions, which aggravates the imbalance of cellular homeostasis and damage to DA neurons.

The accumulation of unfolded, misfolded, and aggregated proteins, and the accumulation induced by cellular stress are essential mechanisms underlying the causes of PD. In this review, we systematically examined the intrinsic molecular links between ER stress, the UPR, and autophagy, as well as the roles of these cross-links in PD pathology.

ER stress, UPR activation, and dysregulated autophagy commonly coexist in patients and various cellular and animal models of PD, and are closely related to DA neurodegeneration caused by PD genetic and neurotoxic factors Table 1. This is why targeting one of these processes would create a beneficial PD treatment Moors et al.

Table 1. The roles and mechanisms of PD-related factors in ER stress, autophagy and their cross-links. Figure 5. Proposed model of cross-links between ER stress, autophagy, and DA neurodegeneration. PD-associated genetic and environmental factors trigger ER stress, and ER stress activates the UPR and induces autophagy to alleviate cellular stress.

However, these PD-associated factors commonly block autophagic flux and impair lysosomal functions, and these changes synergistically cause severe damage and degeneration of DA neurons. For example, administration of GSK, a PERK inhibitor, results in effective neuroprotection and prevents loss of SNpc DA neurons in mice that were treated with PD neurotoxin 6-OHDA Mercado et al.

Gene therapy that restores the folding capacity by administration of viral-mediated overexpression of GRP78 Gorbatyuk et al. Rapamycin, an inhibitor of mTOR, initiates autophagy induction, enhances autophagic flux Rubinsztein and Nixon, , and confers significant protective effects on DA neurons in various PD models Moors et al.

Additionally, enhancing lysosomal biogenesis by TFEB overexpression or pharmacological stimulation of TFEB function by CCI was shown to eliminate α-SYN oligomers and rescue midbrain DA neurons from α-SYN toxicity in rats Decressac et al. It is notable that PD-associated genetic or environmental factors lead to ER stress and UPR activation, which commonly initiate autophagy.

However, these PD-associated factors also block autophagic flux and impair lysosomal functions. An intervention strategy for one of the two processes alone may not completely alleviate the imbalance in cellular homeostasis. GW and XL designed the theme of the manuscript. HR and WZ wrote the manuscript.

All authors approved the submitted version. This research was funded by the National Natural Science Foundation of China , , and , Suzhou Clinical Research Center of Neurological Disease Szzx , and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Thank you for visiting nature. You are Fat-burning mechanisms a browser version with limited Autophavy for CSS. To obtain the best experience, Autophagy and ER stress recommend amd use Autophagy and ER stress more up Autophgay date browser Autopbagy turn off compatibility mode in Internet Explorer. Autophaby the xtress, to ensure amd support, we Autophagy and ER stress displaying the site without styles and JavaScript. Specific molecular interactions that underpin the switch between ER stress-triggered autophagy-mediated cellular repair and cellular death by apoptosis are not characterized. We show that the p53 effector PERP, which specifically induces apoptosis when expressed above a threshold level, has a heterogeneous distribution across the PM of un-stressed cells and is actively turned over by the lysosome. PERP is upregulated following sustained starvation-induced autophagy, which precedes the onset of apoptosis indicating that PERP protein levels are controlled by a lysosomal pathway that is sensitive to cellular physiological state. Autophagy and ER stress

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