Understanding the Role of the Unfolded Protein Response Sensor IRE1 in the Biology of Antigen Presenting Cells

Flores-Santibáñez, Felipe; Medel, Bernardita; Bernales, José Ignacio; Osorio, Fabiola

doi:10.3390/cells8121563

Cited by 13 publications

(10 citation statements)

References 134 publications

(197 reference statements)

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“…Various viral proteins are involved in these processes. The highly conserved IRE1α-dependent UPR is particularly interesting because it has been shown to influence many cellular pathways such as the regulated cell death, autophagy and cytoskeleton dynamics [ 59 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing

Rohde

Pfeiffer

Baumgart

et al. 2022

Viruses

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Ebola (EBOV) and Marburg virus (MARV) are highly pathogenic filoviruses that influence cellular signaling according to their own needs. MARV has been shown to regulate the IRE1α-dependent unfolded protein response (UPR) to ensure optimal virus replication. It was not known whether EBOV affects this signaling cascade, which can be beneficial or detrimental for viruses. Activation of IRE1α leads to the expression of the transcription factor XBP1s, which binds to cis-acting UPR elements (UPRE), resulting in the expression of genes aimed at restoring homeostasis in the endoplasmic reticulum. We observed that EBOV infection, in contrast to MARV infection, led to UPR activation by IRE1α-dependent but not ATF6-dependent signaling. We showed an activation of IRE1α, XBP1s and UPRE target genes upon EBOV infection. ATF6, another UPRE transcription factor, was not activated. UPRE activation was mainly attributed to the EBOV nucleoprotein NP and the soluble glycoprotein sGP. Finally, activation of UPR by thapsigargin, a potent ER-stress inducer, in parallel to infection as well as knock-out of XBP1 had no effect on EBOV growth, while MARV proliferation was affected by thapsigargin-dependent UPR activation. Taken together EBOV and MARV differ in their strategy of balancing IRE1α-dependent signaling for their own needs.

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Section: Discussionmentioning

confidence: 99%

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing

Rohde

Pfeiffer

Baumgart

et al. 2022

Viruses

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“…The pathophysiological role of this cytokine is still unclear, with reports showing a correlation between its expression and clinical score symptoms in human patients 39,41 while others report a protective role for this cytokine during influenza infection in mice [42][43][44] . Moreover, IL-6 has been described as a target gene of the UPR transcription factor sXBP1 during ER stress activation 30,45,46 . In vitro, AAmut/PR8 more potently induces ER stress activation and UPR in accordance with our previous work 24 .…”

Section: Discussionmentioning

confidence: 99%

Optimizing the live attenuated influenza A vaccine backbone for high-risk patient groups

Bonifacio

Williams

Garnier

et al. 2021

Preprint

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The live attenuated influenza vaccine (LAIV) is approved for intranasal spray application in 2-49 year-old patients with safety concerns limiting its use in younger children and immunocompromised patients, mainly from the higher incidence of adverse events and the possibility of uncontrolled replication and reversion to a pathogenic strain, respectively. Further attenuation of the LAIV could generally improve its safety profile, which might come at the cost of reduced immunogenicity. To solve this dilemma, we took advantage of a recently defined mechanism of ER stress induction by modifying IAV non-structural protein 1 (NS1). The modified LAIV (AAmut/PR8) showed stronger ER stress activation in vitro and replicated to lower titers in vivo compared to its parental strain, without affecting protection against homo-subtypic or hetero-subtypic IAV strains. AAmut/PR8 could pose as a suitable strategy to attend the gap to the current LAIV recommendation guidelines in susceptible target populations.

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“…The UPR also regulates inflammation (Bettigole and Glimcher, 2015;Grootjans et al, 2016;Flores-Santibáñez et al, 2019), by mechanisms that could be extended to neurodegeneration (Reverendo et al, 2019). Innate recognition via TLRs triggers ER stress in leukocytes and UPR components amplify the inflammatory program elicited by these receptors (Goodall et al, 2010;Martinon et al, 2010).…”

Section: The Upr In Immune Cell Function In Physiological and Inflammatory Statesmentioning

confidence: 99%

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

Fernández

Geisse

Bernales

et al. 2021

Front. Aging Neurosci.

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Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases.

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Understanding the Role of the Unfolded Protein Response Sensor IRE1 in the Biology of Antigen Presenting Cells

Cited by 13 publications

References 134 publications

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing

Optimizing the live attenuated influenza A vaccine backbone for high-risk patient groups

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

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