Live and let die: signaling AKTivation and UPRegulation dynamics in SARS-CoVs infection and cancer

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. Of particular interest for this topic are the signaling cascades that regulate cell survival and death, two opposite cell programs whose control is hijacked by viral infections. The AKT and the Unfolded Protein Response (UPR) pathways, which maintain cell homeostasis by regulating these two programs, have been shown to be deregulated during SARS-CoVs infection as well as in the development of cancer, one of the most important comorbidities in relation to COVID-19. Recent evidence revealed two way crosstalk mechanisms between the AKT and the UPR pathways, suggesting that they might constitute a unified homeostatic control system. Here, we review the role of the AKT and UPR pathways and their interaction in relation to SARS-CoV-2 infection as well as in tumor onset and progression. Feedback regulation between AKT and UPR pathways emerges as a master control mechanism of cell decision making in terms of survival or death and therefore represents a key potential target for developing treatments for both viral infection and cancer. In particular, drug repositioning, the investigation of existing drugs for new therapeutic purposes, could significantly reduce time and costs compared to de novo drug discovery.

Policy options and practical recommendations for determining priorities in public health research agendas in peripheral countries: insights from a collaborative work initiative in Argentina during the COVID-19 pandemic

“…During this period, we also supplied high quality RBD antigen (through University MTAs) to 9 different institutions across Argentina for use in their basic and applied research projects ( 9 , 10 ). 7 In the meantime, members of the Consortium took part in several outreach activities where not only general COVID-19 information was shared but also results and work perspectives ( 11 ). 8 , 9 Importantly, some results generated by the AntiCovid Consortium contributed to one of the four COVID-19 vaccine project candidates (project called ARGENVAC) funded by the Argentinian Ministry of Science and Technology (MinCyT) to progress in preclinical studies.…”

“…During this period, we also supplied high quality RBD antigen (through University MTAs) to 9 different institutions across Argentina for use in their basic and applied research projects (9,10). In the meantime, members of the Consortium took part in several outreach activities where not only general COVID-19 information was shared but also results and work perspectives (11). , Importantly, some results generated As an additional outcome, researchers established a previously unimplemented network from different bio-scientific fields, fostering new collaborative and positive interactions among their peers.…”

Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration

“…Consequently, this imbalance leads to the accumulation of unfolded proteins, inducing ER stress [13,17]. In response to ER stress, cells activate a multifaceted signaling network known as UPR, an adaptive response aimed at mitigating the burden of unfolded proteins to sustain cellular viability and function [18,19].…”

“…Some examples are the Hepatitis C virus (HCV), which activates the eIF2α/ATF4 pathway, leading to the selective degradation of HCV pro-oxidant proteins Core and NS5A [33]; the Zika virus (ZIKV) activates IRE1, promoting XBP1 mRNA splicing and increasing viral replication [34]. However, the Herpes simplex virus (HSV-1) suppresses the UPR initially (especially the IRE1 pathway and XBP1 activation), and enhances it later during infection, aligning with the replication stages [19,35]. Also, the Porcine delta coronavirus (PDCoV) is able to improve viral replication through the ATF6 pathway, while PERK signaling abrogates it, and IRE1 is not involved in this viral replication [36].…”

The comprehensive SARS-CoV-2 ‘hijackome’ knowledge base— reveals significant changes in host cell protein expression and activation by multiple SARS-CoV-2 variants

“…compartment (ERGIC) and ER. During the viral replication cycle, the SARS-CoV-2 produces a large number of viral proteins, some of which may be misfolded or aberrantly processed (Wong and Saier 2021;Suaya et al 2022). The ERAD pathway recognizes these misfolded viral proteins and targets them for degradation to prevent their accumulation, which can disrupt normal cellular processes and induce cellular stress responses(Byun et al 2014).…”