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.

Keywords: ACE2; COVID-19; GRP78; SARS-CoV-2 infection; cellular signaling/transcription; host factor; metabolic implication; spike protein; viral chaperone; viral co-receptor.

Figure 1

SARS-CoV-2 structure and protein interactions. SARS-CoV-2 is enveloped by a lipid bilayer membrane and consists of several viral proteins [24,25,26]. Recently, we and another research group independently reported that GRP78 functions as a host co-receptor for SARS-CoV-2 infection via complex formation with SARS-CoV-2 spike protein and host receptor ACE2 [12,15]. Cumulative protein interactome data have shown that GRP78 can also interact with other viral proteins of SARS-CoV-2, such as the spike (S), envelope (E), nucleocapsid (N), NSP2, NSP4, NSP14, ORF7a, and ORF8 [16], suggesting its possible involvement in other lifecycle stages and pathology of SARS-CoV-2. The upper right illustration of SARS-CoV-2 was created at the Centers for Disease Control and Prevention (CDC).

Figure 2

Potential roles of GRP78 in the life cycle of SARS-CoV-2. Emerging evidence has shown that GRP78 directly binds with several viral proteins of SARS-CoV-2 [12,15,16,18]. Given the localizations and biological roles, GRP78 could also contribute to various life-cycle stages of SARS-CoV-2, not only the binding but also the endocytosis/entry, replication, translation, assembly, and exocytosis/egress processes.

Figure 3

Potential roles of GRP78 in the cellular signaling and transcription of COVID-19. GRP78 is associated with various cellular signaling and transcription activities involved in inflammation, cytokine release, fibrosis, and cell survival/death [13,51,52,53,54,55]. Thus, the direct and/or indirect activation of GRP78 with ACE2 and other signaling molecules (integrin, Cripto, α2-Macroglobulin, isthmin, etc.) might be associated with the pathology of COVID-19 via the linked intracellular signaling (PI3K, MAPK, ATK, JAK, JNK, etc.) and transcription control (NF-kB, STAT, SMAD2/3, YAP/TAZ, etc.) [51,53,56,58,59,60].

Figure 4

The regulation and metabolic association/implication of GRP78 in COVID-19. Older age, obesity, diabetes, and some types of lung cancer are known to be significant risk factors for COVID-19 severity and mortality [5,6,7,8,9]. Theses pathological conditions increase the expression of GRP78 [21,22,23,61]. SARS-CoV-2 infection is also associated with the overexpression of GRP78 in the lung and circulation [62,74]. The excessive protein production and UPR response in the ER compartment is attributed to GRP78 overexpression via ATF6/XBP1 transcription activity [12,89,90], which triggers the translocation of GRP78 to the cell surface and the circulation [30,31,32]. The excessive expression of GRP78 contributes to metabolic diseases, such as hyperglycemia, hyperinsulinemia, liver steatosis, abnormal lipid control, inflammation, insulin resistance, and diabetes [91,92,93]. Therefore, the infection- and stress-induced GRP78 expression might in part account for the metabolic abnormalities of COVID-19.

Figure 5

Emerging and potential roles of GRP78 in COVID-19. Recent studies have suggested that GRP78 on the cell surface and in circulation acts as a host co-receptor for SARS-CoV-2 infection [12,15], and cumulative protein interactome data have shown that GRP78 also could interact with other viral proteins of SARS-CoV-2 [16]. The expression of GRP78 is highly relevant to COVID-19 risk factors, such as older age, obesity, diabetes, and cancer [12,21,22,23,61]. Given its significant roles in a wide range of biological processes, including protein homeostasis and cellular signaling, GRP78 possibly plays an important role in various viral life cycle stages (binding, entry/endocytosis, replication, translation, assembly, egress/exocytosis, stabilization, etc.) and pathology (inflammation, fibrosis, organ tropism, long COVID, co-/2nd-infection, microbiota, metabolic disorders, etc.) of SARS-CoV-2.