SARS-CoV-2 activates ER stress and Unfolded protein response

Rosa-Fernandes, Livia; Lc, Lázari; Macedo-da-Silvia, J; VdM, Gomes; Rrg, Machado; Af, dos Santos; Db, Araujo; Jvp, Coutinho; Arini, Gabriel Santos; Cb, Angeli; Ee, de Souza; Wrenger, Carsten; Crf, Marinho; Dbl, Oliveira; El, Durigon; Labriola, Letícia; Palmisano, Giuseppe

doi:10.1101/2021.06.21.449284

Cited by 24 publications

(25 citation statements)

References 125 publications

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“…A previous study by our group revealed an activation of the UPR pathway after 6h of SARS-CoV-2 infection 17 , corroborating previous observation of ER-stress enhancement 26 and UPR pathway activation during viral infection 18,19 . Based on these findings, we hypothesized that increased misfolded or unfolded proteins produced during SARS-CoV-2 infection may be tagged for degradation by arginylation in order to maintain cellular homeostasis.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, cytoskeleton proteins were among the experimentally arginylated proteins identified in previous studies (Seo et al 56 and Wong et al 57 ). We monitored the arginylation levels of one major cytoskeleton protein, ACTB, and we observed its increase in the first 2h after infection in Calu-3 cells, with a decrease at 48h, when apoptosis-related proteins were activated 17 . The ACTB arginylation pattern was different in infected Vero cells, as was already observed for phosphorylation 89 .…”

Section: Discussionmentioning

confidence: 99%

“…The intense use of the host's ER during viral replication increases the stress in this compartment, resulting in the accumulation of misfolded proteins and activation of the unfolded protein response (UPR) 15,16 . Recently, we 17 and other groups discovered that SARS-CoV-2 infection also induces ER-stress and may be associated with patient survival 17,18,19 . The UPR pathway is highly conserved and regulates important cellular events such as growth, defense, homeostasis, and cell survival 13,20 .…”

Section: Introductionmentioning

confidence: 95%

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Protein arginylation is regulated during SARS-CoV-2 infection

Macedo-da-Silva

Rosa-Fernandes

Gomes

et al. 2021

Preprint

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In 2019, the world witnessed the onset of an unprecedented pandemic. In September 2021, the infection by SARS-CoV-2 had already been responsible for the death of more than 4 million people worldwide. Recently, we and other groups discovered that SARS-CoV-2 infection induces ER-stress and activation of unfolded protein response (UPR) pathway. The degradation of misfolded/unfolded proteins is an essential element of proteostasis and occurs mainly in lysosomes or proteasomes. The N-terminal arginylation of proteins is characterized as an inducer of ubiquitination and proteasomal degradation by the N-end rule pathway. Here we present, for the first time, data on the role of arginylation during SARS-CoV-2 infection. We studied the modulation of protein arginylation in Vero CCL-81 and Calu-3 cells infected after 2h, 6h, 12h, 24h, and 48h. A reanalysis of in vivo and in vitro public omics data combined with immunoblotting was performed to measure the levels of ATE1 and arginylated proteins. This regulation is seen specifically during infections by coronaviruses. We demonstrate that during SARS-CoV-2 infection there is an increase in the expression of the ATE1 enzyme associated with regulated levels of specific arginylated proteins. On the other hand, infected macrophages showed no ATE1 regulation. An important finding revealed that modulation of the N-end rule pathway differs between different types of infected cells. We also confirmed the potential of tannic acid to reduce viral load, and furthermore, to modulate ATE1 levels during infection. In addition, the arginylation inhibitor merbromin (MER) is also capable of both reducing viral load and reducing ATE1 levels. Taken together, these data show the importance of arginylation during the progression of SARS-CoV-2 infection and open the door for future studies that may unravel the role of ATE1 and its inhibitors in pathogen infection.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Protein arginylation is regulated during SARS-CoV-2 infection

Macedo-da-Silva

Rosa-Fernandes

Gomes

et al. 2021

Preprint

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“…SQSTM1 plays a significant role in tumor transformation due to its important function as a signaling molecule interacting with many oncogenic pathways, including those involving NFE2L2/NRF2 and NFKB/NF-κB [24]. Several studies also reported evidence of mitochondrial dysfunction, excessive production of reactive oxygen species, ER stress, and unfolded protein responses in the cells infected with SARS-CoV-2 [25][26][27]. As mentioned, these pathological events could be, in part, a result of disturbed autophagy flux in the cells.…”

Section: Potential Clues and Mechanisms Supporting The Role Of Sars-cov-2 In Oncogenesismentioning

confidence: 99%

Autophagy: The Potential Link between SARS-CoV-2 and Cancer

Habibzadeh

Dastsooz

Eshraghi

et al. 2021

Cancers

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COVID-19 infection survivors suffer from a constellation of symptoms referred to as post-acute COVID-19 syndrome. However, in the wake of recent evidence highlighting the long-term persistence of SARS-CoV-2 antigens in tissues and emerging information regarding the interaction between SARS-CoV-2 proteins and various components of the host cell macroautophagy/autophagy machinery, the unforeseen long-term consequences of this infection, such as increased risk of malignancies, should be explored. Although SARS-CoV-2 is not considered an oncogenic virus, the possibility of increased risk of cancer among COVID-19 survivors cannot be ruled out. Herein, we provide an overview of the possible mechanisms leading to cancer development, particularly obesity-related cancers (e.g., colorectal cancer), resulting from defects in autophagy and the blockade of the autophagic flux, and also immune escape in COVID-19 survivors. We also highlight the potential long-term implications of COVID-19 infection in the prognosis of patients with cancer and their response to different cancer treatments. Finally, we consider future directions for further investigations on this matter.

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“…3) Induces ER (Endoplasmic Reticulum) Stress activated Unfolded Protein response which leads to the accelerated cell death [1600,1601,1600,1602]. 4) Protein Mutations/Deletions reported [1131,1155].…”

mentioning

confidence: 99%

SARS-COV-2 acts as a test of Air Pollution, Lifestyle Disorders and Immune Tolerance dysregulation in human body

Karthik¹

2021

Preprint

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SARS-COV-2 is reported to be associated with severe immune dysregulation, delayed humoral responses and accelerated innate immune response mediated damages. As the pandemic is turning the world upside down, In order to address this disease we should first get an insight into the mechanism of action through which SARS-COV-2 is achieving the above said dysregulating or modulating effects on human immune system. T his article presents the basic or skeletal mechanism through which SARS-COV-2 dysregulates immune system by targeting innate immune system, adaptive immune system and different immune tolerance check points by dysregulating different miRNA’s and the preexisting conditions or comorbidities of the patients. This article comprises of the comparative and comprehensive literature review targeting all topics with the data available/reported till date in the scientific community.

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SARS-CoV-2 activates ER stress and Unfolded protein response

Cited by 24 publications

References 125 publications

Protein arginylation is regulated during SARS-CoV-2 infection

Protein arginylation is regulated during SARS-CoV-2 infection

Autophagy: The Potential Link between SARS-CoV-2 and Cancer

SARS-COV-2 acts as a test of Air Pollution, Lifestyle Disorders and Immune Tolerance dysregulation in human body

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