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Review
. 2023 Sep 30;32(3):183-196.
doi: 10.7570/jomes23053.

COVID-19, Obesity, and GRP78: Unraveling the Pathological Link

Jihoon Shin  1   2   3 , Iichiro Shimomura  1
Affiliations
Review

COVID-19, Obesity, and GRP78: Unraveling the Pathological Link

Jihoon Shin et al. J Obes Metab Syndr. .

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to an unprecedented global surge in infections and fatalities. Notably, obesity has emerged as an important susceptibility factor for COVID-19; however, the pathological mechanisms for this remain poorly understood. Recent studies proposed a role for glucose-regulated protein 78 (GRP78), a protein implicated in both obesity and metabolic syndrome, which may function as a binding partner and/or co-receptor for SARS-CoV-2. Given its crucial involvement in diverse biological processes, GRP78 likely plays a major role in multiple facets of the viral life cycle and the pathology of COVID-19. This perspective review discusses the potential contributions of GRP78 to the dynamics of SARS-CoV-2 infection and pathology, particularly in the context of obesity. The primary objective is to facilitate a deeper understanding of the pathogenesis of COVID-19. Through this exploration, we aim to illuminate the complex interactions underpinning the nexus of COVID-19, obesity, and GRP78, ultimately paving the way for informed therapeutic strategies and preventive measures.

Keywords: COVID-19; GRP78; Obesity; SARS-CoV-2.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unparalleled global upsurge in infections and fatalities. Notably, obesity has emerged as an important susceptibility factor for COVID-19, with its prevalence continuing to rise substantially on a global scale. However, the underlying pathological mechanisms remain incompletely elucidated. Recent research suggests that glucose-regulated protein 78 (GRP78), a protein widely associated with obesity and metabolic syndrome, may play a pivotal role as both a binding partner and co-receptor for SARS-CoV-2. Given its pivotal involvement in a range of biological processes, GRP78 likely assumes a multifaceted role in the viral lifecycle. In addition to its functions as a binding partner and co-receptor, GRP78 also operates as a viral chaperone, cellular signaling mediator, and protein stabilizer. These diverse roles may contribute to the various pathologies observed in COVID-19, encompassing not only infection dynamics but also aspects such as inflammation, fibrosis, organ tropism, long COVID syndrome, co/secondary infections, and metabolic abnormalities.
Figure 2
Figure 2
Glucose-regulated protein 78 (GRP78) plays a multifaceted role as a host factor that affects various stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle. It functions as a co-receptor, chaperone, protein stabilizer, and intermediary in cellular signaling and transcription processes. On the cell surface, GRP78 binds to the spike protein of SARS-CoV-2, triggering endocytosis and facilitating viral entry. Within the endoplasmic reticulum (ER), GRP78 assists in replicating and assembling viral proteins. It may also play a role in the exocytosis/egress of the virus and contribute to its overall stability, supporting a successful viral life cycle. Moreover, the interaction between SARS-CoV-2 and cell surface GRP78 could potentially activate cellular signaling pathways associated with inflammation and fibrosis. These pathways, in turn, may lead to the tissue and organ damage observed in coronavirus disease 2019 (COVID-19). ACE2, angiotensin-converting enzyme 2; ERGIC, ER–Golgi intermediate compartment.
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