Mini review ATF4 and GRP78 as novel molecular targets in ER-Stress modulation for critical COVID-19 patients

Abstract

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 4.4 million deaths worldwide as of August 24, 2021. Viral infections such as SARS-CoV2 are associated with endoplasmic reticulum (ER) stress and also increased the level of reactive oxygen species. Activating transcription factor 4 (ATF4) is preferentially translated under integrated stress conditions and controls the genes involved in protein homeostasis, amino acid transport and metabolism, and also protection from oxidative stress. The GRP78, regulated either directly or indirectly by ATF4, is an essential chaperone in the ER and overexpressed and appears on the surface of almost all cells during stress and function as a SARS-CoV2 receptor. In this mini-review article, we briefly discuss the effects of SARS-CoV2 infection on the ER stress, and then the stress modulator functions of ATF4 and GRP78 as novel therapeutic targets were highlighted. Finally, the effects of GRP78 inhibitory components as potential factors for targeted therapies for COVID-19 critical cases were discussed. Keywords COVID-19 disease • ER stress modulation • ATF4 • GRP78 targeting COVID-19 infection and ER stressThe SARS-CoV-2 is a member of Coronaviridae, a kind of enveloped viruses with positive-sense, single-stranded RNA [1]. This virus caused more than 4.4 million deaths worldwide up to August 2021. No specific therapeutic treatment for COVID-19 has been approved so far which highlighting the urgent need to identify new antiviral strategies.

Soluble RAGE as a Prognostic Marker of Worsening in Patients Admitted to the ICU for COVID-19 Pneumonia: A Prospective Cohort Study

“…In our study, no association was observed regarding GRP78 and ICU outcome. GRP78 is an essential chaperone protein involved in the unfolded protein response (UPR) and its expression is regulated by activating transcription factor 4, which is activated in stress situations where there is a risk of protein misfolding, such as oxidative stress, anoxia/hypoxia, acute inflammation and amino acid deprivation [ 16 ]. UPR consists of a decrease in protein synthesis and an enhanced capacity of endoplasmic reticulum protein folding, in order to maintain cellular homeostasis.…”

“…ERS has been described to be associated with organ failure in patients suffering from a systemic inflammation response during septic shock or cardiac surgery with cardiopulmonary bypass [ 12 , 13 ]. SARS-CoV-2 infection and replication within the host cell may compete with the normal folding process, and may be responsible for both GRP78 overexpression and an increased unfolded protein response [ 14 , 15 , 16 , 17 ]. However, there are currently no data describing the GRP78 level in COVID-19 ICU patients.…”

Comparison of allosteric signaling in DnaK and BiP using mutual information between simulated residue conformations

“…[98][99][100][101] Our observations deepen our understanding of allosteric communication in the Hsp70 system and how a ubiquitous but diverse protein class has adapted to different cellular environments and cochaperone interaction partners. As Hsp70 have also been suggested to be promising therapeutic factors in a range of contexts, among them neurodegenerative diseases 2,3,[7][8][9][10][11][12] and csBiP as a coreceptor of the pandemic SARS-CoV-2 virus, [40][41][42][43][44] investigating such evolutionary differences in further detail may become a key step in developing medical applications.…”

“…[32][33][34] Tumors and cells under stress show elevated levels of csBiP compared to normal cells, which has prompted investigations into applications for cancer detection and therapy. [35][36][37][38][39] Moreover, csBiP is implicated as a coreceptor promoting host cell entry for several coronaviruses, including the pandemic virus SARS-CoV-2, [40][41][42][43][44] and has been suggested as a therapeutic factor for severe COVID-19 cases. 41,44 Elucidating the evolutionary differences distinguishing Hsp70 variants could deepen our understanding of this important protein class and help to tailor drugs to the specific properties of the targeted protein.…”

“…[35][36][37][38][39] Moreover, csBiP is implicated as a coreceptor promoting host cell entry for several coronaviruses, including the pandemic virus SARS-CoV-2, [40][41][42][43][44] and has been suggested as a therapeutic factor for severe COVID-19 cases. 41,44 Elucidating the evolutionary differences distinguishing Hsp70 variants could deepen our understanding of this important protein class and help to tailor drugs to the specific properties of the targeted protein. The sequence homology between BiP and DnaK is below 50%, while several functional differences have been reported between the two variants, such as propensity of NBD-SBD docking, post-translational modifications or interactions with cochaperones modulating allosteric signaling.…”