UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

Kopp, Megan C.; Larburu, Natacha; Durairaj, Vinoth; Adams, Christopher J.; Ali, Maruf M. U.

doi:10.1038/s41594-019-0324-9

Cited by 249 publications

(188 citation statements)

References 34 publications

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“…PERK (encoded by the Eif2ak3 gene) is a type I ER transmembrane protein, its protein kinase activity at the carboxyl terminus of its cytoplasmic segment is the main functional region and can phosphorylate eIF2α at protein serine 51 and also autophosphorylate 4,43 . The role of PERK in skeletal development and remodeling has been widely concerned.…”

Section: Discussionmentioning

confidence: 99%

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

et al. 2020

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Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

et al. 2020

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“…This is further complimented by pull-down interaction analysis and chemical cross-linking that similarly observe a direct interaction with BiP NBD [ 50 ]. A recent structure-guided mutational study identified a mutation within the NBD that severely reduced the affinity for binding to IRE1 [ 51 ]. Furthermore, in another mutational-based study that was conducted in yeast cells, it was suggested that the interaction with IRE1 was again mediated via BiP NBD [ 52 ].…”

Section: Hsp70 Specialized Interactions At the Membranementioning

confidence: 99%

Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response

et al. 2020

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Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones. There are numerous homologues and isoforms of Hsp70 that participate in a wide variety of cellular functions. This diversity can facilitate adaption or specialization based on particular biological activity and location within the cell. In this review, we highlight two specialized binding partner proteins, Tim44 and IRE1, that interact with Hsp70 at the membrane in order to serve their respective roles in protein translocation and unfolded protein response signalling. Recent mechanistic data suggest analogy in the way the two Hsp70 homologues (BiP and mtHsp70) can bind and release from IRE1 and Tim44 upon substrate engagement. These shared mechanistic features may underlie how Hsp70 interacts with specialized binding partners and may extend our understanding of the mechanistic repertoire that Hsp70 chaperones possess.

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“…In non-stressed cells, the highly abundant major ER chaperone and ER stress sensor binding-immunoglobulin protein BiP (also called 78 kDa glucoseregulated protein, GPR78; heat shock protein family A member 5, HSPA5) binds to PERK and IRE1α, which keeps these two proteins in an inactive monomeric state (Bertolotti et al, 2000;Pobre et al, 2019). Upon increased binding of BiP to misfolded ER clients, BiP is released from both PERK and IRE1α, resulting in an (indirect) activation of the two kinases by oligomerization and trans(auto)phosphorylation (Carrara et al, 2015;Cui et al, 2011;Kopp et al, 2019). Active PERK phosphorylates the eukaryotic translation initiation factor 2 (eIF2) subunit α to shut down translation and also activates ATF4, the master transcription factor orchestrating ER stressinduced genes (Han et al, 2013;Urra & Hetz, 2017).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Shaban

Müller

Mayr-Buro

et al. 2020

Preprint

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Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.One Sentence Summary / Running titleSuppression of coronavirus replication through thapsigargin-regulated ER stress, ERQC / ERAD and metabolic pathways

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UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

Cited by 249 publications

References 34 publications

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function

Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response

Inhibiting coronavirus replication in cultured cells by chemical ER stress

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