Modulation of cell proteome by 25-hydroxycholesterol and 27-hydroxycholesterol: A link between cholesterol metabolism and antiviral defense

Abstract

A B S T R A C TPhysiological cholesterol metabolism implies the generation of a series of oxidized derivatives, whose oxysterols are by far the most investigated ones for their potential multifaceted involvement in human pathophysiology. In this regard, noteworthy is the broad antiviral activity displayed by defined side chain oxysterols, in particular 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC). Although their antiviral mechanism(s) may vary depending on virus/host interaction, these oxysterols share the common feature to hamper viral replication by interacting with cellular proteins. Here reported is the first analysis of the modulation of a cell proteome by these two oxysterols, that, besides yielding additional clues about their potential involvement in the regulation of sterol metabolism, provides novelinsights about the mechanism underlying the inhibition of virus entry and trafficking within infected cells. We show here that both 25HC and 27HC can down-regulate the junction adhesion molecule-A (JAM-A) and the cation independent isoform of mannose-6-phosphate receptor (MPRci), two crucial molecules for the replication of all those viruses that exploit adhesion molecules and the endosomal pathway to enter and diffuse within target cells.

The cholesterol metabolite 27-hydroxycholesterol inhibits SARS-CoV-2 and is markedly decreased in COVID-19 patients

“…Thus, 27OHC is modifying structure and most likely function of these crucial membrane lipid-protein clusters, where by the way the ACE-2 receptor exploited by SARS-CoV-2 to enter the target cells is located [ 30 ], and it certainly induces a modification of multivesicular endosome biogenesis, that by lipid rafts is regulated [ 31 ]. Further, we very recently observed in HeLa cells a significant 27OHC-dependent down-regulation of cation independent isoform of mannose-6-phosphate receptor (MPRci) [ 11 ], a transporter located at late endosomes whose activity appears crucial for all viruses exploiting the endosomal way to enter and diffuse within cells [ [32] , [33] , [34] ]. All together, these facts and findings point to the inhibition of virus entry as the primary protective mechanism of 27OHC externally added to cells.…”

“…Oxysterols such as 25-hydroxycholesterol (25OHC) have shown to markedly inhibit the replication of a large variety of both enveloped and non-enveloped human viral pathogens [ [5] , [6] , [7] ]. However, another oxysterol of enzymatic origin, namely 27-hydroxycholesterol (27OHC), is gaining increasing consideration as a protective molecule not only against the respiratory virus Rhinovirus, but also against a wide range of other viral infections [ [8] , [9] , [10] , [11] ]. There is clear evidence that exogenously added 27OHC accumulates in plasma membrane lipid rafts, likely affecting viral entry but also modulating cell signaling stemming from such microdomains [ 12 , 13 ].…”

Oxysterols in the Immune Response to Bacterial and Viral Infections

“…Apart from 25-OHC, 27-OHC has also been gaining attention for having broad antiviral activity against several viruses, such as murine cytomegalovirus [ 26 ], human papillomavirus [ 43 ], rhinoviruses [ 43 ], herpes simplex-1 virus [ 45 ], rotavirus [ 46 ], and SARS-CoV-2 [ 47 ], among others [ 43 ]. Mechanistically, in vitro studies suggest that the antiviral activity of 27-OHC is multifactorial, including interfering with viral entry into the cell, inducing cholesterol remodeling on plasma membranes and endosomes, and regulating adhesion molecules [ 42 ] and pro-inflammatory cytokine production [ 45 ].…”

Effect of industrial processing and storage procedures on oxysterols in milk and milk products

“…[3][4][5] Over the last few years, growing evidence is clearly indicating how only oxysterols of enzymatic origin and in particular the side chain oxysterols 25-hydroxycholesterol and 27-cholesterol may have a pleiotropic physiological role. 6,7 Non-enzymatic oxysterols, in particular 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC), have been defined as accurate markers of cholesterol auto-oxidation, as their concentration heavily increases during inflammation and other processes characterized by cell and tissue oxidative stress. [8][9][10] In this relation, it is worth outlining that cholesterol oxidation products (COPs) often measured in foodstuffs belong to the not enzymatic oxysterol sub-family.…”