Thiol Modifications in the Extracellular Space-Key Proteins in Inflammation and Viral Infection

Abstract

Posttranslational modifications (PTMs) allow to control molecular and cellular functions in response to specific signals and changes in the microenvironment of cells. They regulate structure, localization, stability, and function of proteins in a spatial and temporal manner. Among them, specific thiol modifications of cysteine (Cys) residues facilitate rapid signal transduction. In fact, Cys is unique because it contains the highly reactive thiol group that can undergo different reversible and irreversible modifications. Upon inflammation and changes in the cellular microenvironment, many extracellular soluble and membrane proteins undergo thiol modifications, particularly dithiol-disulfide exchange, S-glutathionylation, and S-nitrosylation. Among others, these thiol switches are essential for inflammatory signaling, regulation of gene expression, cytokine release, immunoglobulin function and isoform variation, and antigen presentation. Interestingly, also the redox state of bacterial and viral proteins depends on host cell-mediated redox reactions that are critical for invasion and infection. Here, we highlight mechanistic thiol switches in inflammatory pathways and infections including cholera, diphtheria, hepatitis, human immunodeficiency virus (HIV), influenza, and coronavirus disease 2019 (COVID-19).

Keywords: S-glutathionylation; S-nitrosylation; disulfide bond; extracellular; infection; inflammation; redox signaling; thiol switch.

Figure 1

Selected thiol modifications in the regulation of the inflammatory response. Posttranslational modifications such as S-glutathionylation and S-nitrosylation occur on intracellular and extracellular proteins. Many ligands for membrane-bound receptors such as receptors for advanced glycation end products (RAGE), Toll-like receptor (TLR), and receptor tyrosine kinase (RTK) undergo redox regulation. Nitrosylated, oligomeric Surfactant protein D (SP-D) binds and inhibits TLR. Heat shock proteins (HSPs) 60 and 70, High-mobility group box 1 (HMGB1), and Peroxiredoxin (Prx) are glutathionylated. They bind to RAGE or TLR, inducing similar downstream-signaling components Tumor necrosis factor receptor–associated factor (TRAF), Nuclear Factor-kappa-B essential modulator (NEMO), Nuclear Factor-kappa-B (NFκB) and eventually a pro-inflammatory response. The RAGE receptor can also activate the NEMO complex via RAS. Also, the TLR pathway can be activated through the Phosphoinositide 3-kinases (PI3K) pathway. PI3K binds to the receptor, which inhibits TRAF6 and activates the serine/threonine-protein kinases (Akt) pathway by activating NEMO. Different components of this pathway can be glutathionylated or nitrosylated. Nitrosylated myeloid differentiation primary response 88 (MyD88) leads to the detaching of the receptor whereby the signal is inhibited. Nitrosylated or glutathionylated IKKβ, p50, and ReIA/p65 lead to their inactivation, eventually inhibiting gene expression.