A tale of two proteins: PACT and PKR and their roles in inflammation

Chukwurah, Evelyn; Farabaugh, Kenneth T.; Guan, Bo‐Jhih; Ramakrishnan, Parameswaran; Hatzoglou, Maria

doi:10.1111/febs.15691

Cited by 39 publications

(33 citation statements)

References 249 publications

(343 reference statements)

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“…The mechanisms by which PSMC3 variants activate PKR in NDD/ID affected individuals remain unclear, but our data open the possibility that PKR may sense a broader spectrum of danger signals than initially assumed, including perturbations of protein homeostasis. This concept is in line with the observation that activated PKR was found in the CNS of subjects with neurodegenerative diseases [89–92] and that neurodegeneration is associated with neuroinflammation [93, 94]. Altogether, our work demonstrates that heterozygous PSMC3 dominant variants result in a neurodevelopmental syndrome associated with a specific type I IFN gene signature.…”

Section: Discussionsupporting

confidence: 90%

De novo variants in thePSMC3proteasome AAA-ATPase subunit gene cause neurodevelopmental disorders associated with type I interferonopathies

Ebstein

Küry

Most

et al. 2021

Preprint

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A critical step in preserving protein homeostasis by the ubiquitin-proteasome system (UPS) is the recognition, binding, unfolding, and translocation of protein substrates by AAA-ATPase proteasome subunits for degradation by 26S proteasomes. Here, we identified fourteen different de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit Rpt5 in twenty-two unrelated heterozygous subjects with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Indeed, depletion of PSMC3 impaired reversal learning capabilities in a Drosophila model. The PSMC3 variants cause proteasome dysfunction in patient-derived cells by disruption of substrate translocation, proteotoxic stress and proteostatic imbalances, as well as alterations in proteins controlling developmental and innate immune programs. Molecular analysis confirmed the induction of cellular stress responses and dysregulated mitophagy along with an elevated type I interferon (IFN) signature. Our data define PSMC3 variants as the genetic cause of proteotoxic stress alerting the innate immune system to mount a type I IFN response and link neurodevelopmental syndromes to interferonopathies.

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Section: Discussionsupporting

confidence: 90%

De novo variants in thePSMC3proteasome AAA-ATPase subunit gene cause neurodevelopmental disorders associated with type I interferonopathies

Ebstein

Küry

Most

et al. 2021

Preprint

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“…ISGF3 translocates to the nucleus where it activates the transcription of IFN-stimulated genes (ISGs) ( 2 ). PKR is an ISG that binds to dsRNA and phosphorylates the α subunit of the eukaryotic initiation factor 2 (eIF2α) leading to general protein synthesis inhibition in order to restore cellular homeostasis upon viral infection ( 6 ). Moreover, it has been described that PKR interacts with several members of the TRAF family involved in MAVS signalling, such as TRAF2 and TRAF6 ( 7 ), and further contributing to the IFN response, it can also mediate phosphorylation of STAT1 ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

et al. 2021

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Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This effect was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reveal a new mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.

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“…PACT, also known as PRKRA, a dsRNA-binding protein harboring three tandem repeats of dsRNA binding motifs, has initially been identified as a direct protein activator of PKR through their heterodimerization in response to diverse stress signals, leading to inhibition of protein translation ( Patel and Sen 1998 ; Patel et al 2000 ). Although PACT activation of PKR and its impact on proinflammatory response have been well documented ( Chukwurah et al 2021 ), more recent studies have also reported a negative regulatory role for PACT on PKR activation ( Clerzius et al 2013 ; Dickerman et al 2015 ; Meyer et al 2018 ). Phenotypic defects in PACT-deficient mice can be rescued by additional knockout of PKR or expression of a dominant-negative mutant of PKR, suggesting a primary function of PACT as a suppressor of aberrant PKR activation ( Dickerman et al 2015 ).…”

Section: Rna-binding Protein Partners Of Rna Sensorsmentioning

confidence: 99%

“…PKR is a dsRNA-activated serine–threonine kinase that plays a major role in a number of different cellular processes such as mRNA translation, transcriptional control, regulation of apoptosis, and proliferation (for reviews, see Gal-Ben-Ari et al 2018 ; Chukwurah et al 2021 ). Particularly, PKR is well-known for its role as a key innate immune sensor.…”

Section: Rna-binding Protein Partners Of Rna Sensorsmentioning

confidence: 99%

Cytoplasmic RNA sensors and their interplay with RNA-binding partners in innate antiviral response: theme and variations

Chan

Jin

2022

RNA

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Sensing of pathogen-associated molecular patterns including viral RNA by innate immunity represents the first line of defense against viral infection. In addition to RIG-I-like receptors and NOD-like receptors, several other RNA sensors are known to mediate innate antiviral response in the cytoplasm. Double-stranded RNA-binding protein PACT interacts with prototypic RNA sensor RIG-I to facilitate its recognition of viral RNA and induction of host interferon response, but variations of this theme are seen when the functions of RNA sensors are modulated by other RNA-binding proteins to impinge on antiviral defense, proinflammatory cytokine production and cell death programs. Their discrete and coordinated actions are crucial to protect the host from infection. In this review, we will focus on cytoplasmic RNA sensors with an emphasis on their interplay with RNA-binding partners. Classical sensors such as RIG-I will be briefly reviewed. More attention will be brought to the new insights on how RNA-binding partners of RNA sensors modulate innate RNA sensing and how viruses perturb the functions of RNA-binding partners.

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A tale of two proteins: PACT and PKR and their roles in inflammation

Abstract: I-like receptor signaling, as well as inflammasome activation. We go on to discuss the specific roles that PKR and PACT play in such proinflammatory signaling, as well as in metabolic syndrome-and environmental stress-induced inflammation.

Cited by 39 publications

References 249 publications

De novo variants in thePSMC3proteasome AAA-ATPase subunit gene cause neurodevelopmental disorders associated with type I interferonopathies

De novo variants in thePSMC3proteasome AAA-ATPase subunit gene cause neurodevelopmental disorders associated with type I interferonopathies

Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

Cytoplasmic RNA sensors and their interplay with RNA-binding partners in innate antiviral response: theme and variations

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