Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

Abstract

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.

Keywords: Endoplasmic reticulum; IRE1; PERK; Spliced XBP1; Unfolded protein response.

Scheme 1

SARS-CoV-2 spike protein interacts with the lung epithelial cells through Angiotensin-Converting Enzyme 2 (ACE2) and being internalized to the cells via endocytosis. SARS-CoV-2 uses intracellular trafficking and double membrane vesicles (DMVs) for replication. During the process of viral replication possibly DMVs carrying viral particles interacts with ER chaperons (ATF6 = activating transcription factor 6; IRE1 = inositol requiring enzyme-1; PERK = PKR-like endoplasmic reticulum kinase; GRP78(BiP) = binding immunoglobulin protein). and initiates unfolded protein response (UPR). In addition, the protein load to the ER protein synthesis machinery during viral protein synthesis can possibly induce production of unfolded protein and initiate UPR during SARS-CoV2 infection. Inhibitors of the PERK (GSK-PERK inhibitor) and IRE1 RNAase activity (MKC8866) can regulate the UPR response in infected cells through modulating the innate immunity and the cellular secretome, respectively. Therefore, these inhibitors hold promise as potential therapeutics for controlling Covid-19 infection. [eIF2α = eukaryotic translation initiation factor 2 alpha; XBP1s = spliced X-box binding protein 1].