Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex

Berwal, Sunil K.; Bhatia, Varsha; Bendre, Ameya D.; Suresh, C. G.; Chatterjee, Sangeeta; Pal, Jayanta K.

doi:10.1016/j.ijbiomac.2018.06.204

Cited by 7 publications

(4 citation statements)

References 44 publications

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“…While a comparably broad variety of signaling pathways was assumed to be involved in oxidative stress response, some effectors are considered to be of particular importance [ 143 ]. One of these effectors is Heme-regulated eIF2α kinase ( HRI ), a redox-sensitive kinase that is autophosphorylated via a heme-dependent mechanism and forms active heterodimers with Heat shock protein 90 (Hsp90) [ 144 ]. Upon its activation, the HRI/Hsp90 complex mediates eIF2α-phosphorylation and thus induces the integrated stress response (ISR) [ 18 ].…”

Section: Oxidative Stress Responsementioning

confidence: 99%

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

Mensch

Zierz

2020

IJMS

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Cellular stress has been considered a relevant pathogenetic factor in a variety of human diseases. Due to its primary functions by means of contractility, metabolism, and protein synthesis, the muscle cell is faced with continuous changes of cellular homeostasis that require rapid and coordinated adaptive mechanisms. Hence, a prone susceptibility to cellular stress in muscle is immanent. However, studies focusing on the cellular stress response in muscular disorders are limited. While in recent years there have been emerging indications regarding a relevant role of cellular stress in the pathophysiology of several muscular disorders, the underlying mechanisms are to a great extent incompletely understood. This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases. Potential mechanisms, as well as involved pathways are critically discussed, and respective disease models are addressed. Furthermore, relevant therapeutic approaches that aim to abrogate defects of cellular stress response in muscular disorders are outlined.

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Section: Oxidative Stress Responsementioning

confidence: 99%

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

Mensch

Zierz

2020

IJMS

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“…Based on our previous work, which demonstrated a key role for the heat shock protein (HSP) HSPB8 in HRIdependent control of innate immune receptor scaffolds (11), it is conceivable that similar mechanisms involving HSPs contribute to the effects observed here. For instance, it is possible that the displacement of HSPs from HRI to cytosolic protein aggregates contributes to the activation of HRI, as previously suggested in the case of Hsc70 and Hsp90 (32,(37)(38)(39)(40). Then, ISR-dependent transcriptional reprogramming could result in the upregulation of specific HSPs that help in the protein refolding and autophagic clearance of protein cargos through the CASA pathway.…”

Section: Discussionmentioning

confidence: 81%

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Mukherjee

Ramaglia

Abdel-Nour

et al. 2021

Journal of Biological Chemistry

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Large cytosolic protein aggregates are removed by two main cellular processes, autophagy and the ubiquitin-proteasome system (UPS), and defective clearance of these protein aggregates results in proteotoxicity and cell death. Recently, we found that the eIF2α kinase heme-regulated inhibitory (HRI) induced a cytosolic unfolded protein response (cUPR) to prevent aggregation of innate immune signalosomes, but whether HRI acts as a general sensor of proteotoxicity in the cytosol remains unclear. Here we show that HRI controls autophagy to clear cytosolic protein aggregates when the UPS is inhibited. We further report that silencing HRI expression resulted in decreased levels of BAG3 and HSPB8, two proteins involved in chaperone-assisted selective autophagy (CASA), suggesting that HRI controls proteostasis in the cytosol at least in part through CASA. Moreover, knocking down the expression of HRI resulted in cytotoxic accumulation of over-expressed α-synuclein, a protein known to aggregate in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. In agreement with these data, protein aggregate accumulation and microglia activation were observed in the spinal cord white matter of 7-month old Hri-/- mice as compared to Hri+/+ littermates. Moreover, aged Hri-/- mice showed accumulation of misfolded α-synuclein, indicative of misfolded proteins, in the lateral collateral pathway, a region of the sacral spinal cord horn that receives visceral sensory afferents from the bladder and distal colon, a pathological feature common to α-synucleinopathies in humans. Together, these results suggest that HRI contributes to a general cUPR that could be leveraged to bolster the clearance of cytotoxic protein aggregates.

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“…Physiological or pathological conditions that increase the accumulation of mistranslated or unfolded proteins lead to ER stress-mediated activation of PERK [ 25 , 29 ]. Heme deficiency [ 26 , 30 ], oxidative stress [ 26 , 31 ] and heat shock [ 32 , 33 , 34 ] activate the HRI kinase. The ISR kinases are regulated by distinct stressors; however, their catalytic kinase domain phosphorylates eIF2α, allowing stress signals to converge on translation initiation inhibition, which is a critical step in translational control.…”

Section: Cellular Stress Response and Translationmentioning

confidence: 99%

Cellular Stress: Modulator of Regulated Cell Death

Lamichhane,

Samir

2023

Biology

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Cellular stress response activates a complex program of an adaptive response called integrated stress response (ISR) that can allow a cell to survive in the presence of stressors. ISR reprograms gene expression to increase the transcription and translation of stress response genes while repressing the translation of most proteins to reduce the metabolic burden. In some cases, ISR activation can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs). ISR and SGs can inhibit apoptosis, pyroptosis, and necroptosis, suggesting that they guard against uncontrolled regulated cell death (RCD) to promote organismal homeostasis. However, ISR and SGs also allow cancer cells to survive in stressful environments, including hypoxia and during chemotherapy. Therefore, there is a great need to understand the molecular mechanism of the crosstalk between ISR and RCD. This is an active area of research and is expected to be relevant to a range of human diseases. In this review, we provided an overview of the interplay between different cellular stress responses and RCD pathways and their modulation in health and disease.

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Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex

Cited by 7 publications

References 44 publications

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

Cellular Stress: Modulator of Regulated Cell Death

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