GRP78, a Novel Host Factor for SARS-CoV-2: The Emerging Roles in COVID-19 Related to Metabolic Risk Factors

Abstract

The outbreak of coronavirus disease 19 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented amount of infection cases and deaths, leading to the global health crisis. Despite many research efforts, our understanding of COVID-19 remains elusive. Recent studies have suggested that cell surface glucose-regulated protein 78 (GRP78) acts as a host co-receptor for SARS-CoV-2 infection and is related to COVID-19 risks, such as older age, obesity, and diabetes. Given its significance in a wide range of biological processes, such as protein homeostasis and cellular signaling, GRP78 might also play an important role in various stages of the viral life cycle and pathology of SARS-CoV-2. In this perspective, we explore the emerging and potential roles of GRP78 in SARS-CoV-2 infection. Additionally, we discuss the association with COVID-19 risks and symptoms. We hope this review article will be helpful to understand COVID-19 pathology and promote attention and study of GRP78 from many clinical and basic research fields.

SARS-CoV2 infection triggers reactive astrocyte states and inflammatory conditions in long-term Human Cortical Organoids

“…Next, we analyzed the level of expression of known SARS-CoV2 receptors and co-receptors in the hCOs. RNA sequencing of late stage (6M) hCOs confirmed low expression of the major SARS-CoV2 receptor, ACE2 2,16,17 , and higher expression of some of the SARS-CoV2 coreceptors such as NRP1, CD147/BSG; GRP78/HSPA5; DPP4 and AXL 7,16,[18][19][20][21][22][23][24][25][26] as well as some of the enzymes involved in the cleavage of the SARS-CoV2 virus spike protein to mediate viral entry to the cell, such as transmembrane serine protease 2 (TMPRSS2), cathepsin B (CTSB), cathepsin L (CTSL) and furin 14,23 (Fig. 1M).…”

“…However, the expression of ACE2 co-receptors that potentiate SARS-CoV2 infectivity has been reported in a number of tissues including the brain. These co-receptors include neuropilin 1 (NRP1) cell surface receptor 16,18–20 , dypeptidylpeptidase 4 (DPP4) 21 , tyrosine-protein kinase receptor UFO (AXL) 22 , the transmembrane glycoprotein (CD147/BSG) 7,23,24 , stress-inducible ER chaperone (GRP78/HSPA5) 25,26 . These reports support the possibility that alternative receptors and co-receptors are mediating SARS-CoV2 entry in brain cells.…”

Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors

“…Specific receptors within the immune system, including Neuropilin-1 (NRP1), C-lectin type receptors (CLR) such as mannose receptor (MR), dendritic cellspecific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), homologous dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin-related (L-SIGN), and macrophage galactose-type lectin (MGL), along with Toll-like receptors (TLRs) including TLR1, TLR4, and TLR6, have been identified as receptors in SARS-CoV-2 [43]. Additionally, non-immune receptors such as the glucose regulated protein 78 (GRP78) have been implicated in the viral process [44]. Moreover, Ezrin and Dipeptidyl peptidase-4 (DPP4) have been suggested as potential targets against SARS-CoV-2, although their roles remain unconfirmed [45].…”

Unveiling the dark side of glucose-regulated protein 78 (GRP78) in cancers and other human pathology: a systematic review

“…A different clinical study, involving a significant number of participants, demonstrated that COVID-19 patients exhibited GRP78 levels approximately five times greater than those observed in the healthy control group Recent research has demonstrated that in addition to the receptor ACE2, csGRP78 can function as a co-receptor for the SARS-CoV-2 spike protein. In order to enter target cells more easily, csGRP78 forms a protein complex on the cell surface with the host cell receptor ACE2 and directly interacts with the SARSCoV-2 spike protein (Shahriari-Felordi et al 2022 ; Sabirli et al 2021 ; Shin et al 2021 , 2022a ; Carlos et al 2021 ; Shin et al 2022a , b ) 17 Ovarian Cancer Cell survival, angiogenesis, chemoresistance GRP78 enhances cell survival, promotes angiogenesis, and contributes to resistance to chemotherapy in ovarian cancer. GRP78 enhances cell survival by activating pro-survival signaling pathways, such as the PI3K/AKT pathway.…”