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Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding

halcyon

Senior Member
Messages
2,482
http://www.pnas.org/content/early/2015/09/25/1515966112
Significance
The innate immune system protects the host against infections with a diverse set of microbes that include intracellular bacterial and protozoan pathogens residing within pathogen-containing vacuoles (PVs). Because PVs provide an intracellular niche permissive for microbial growth, their destruction is critical for host defense. In mammals, PV destruction is dependent on immunity-related GTPases and guanylate binding proteins (GBPs). Although it has been shown that GBPs translocate to and eliminate PVs, the mechanisms by which GBPs specifically bind to PVs were unknown. Here, we describe an immune pathway that results in the decoration of PVs with a small protein called ubiquitin. Ubiquitin-decorated PVs are subsequently recognized by GBPs, resulting in the elimination of PVs and their microbial inhabitants.

Abstract
Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.
 

Hip

Senior Member
Messages
17,824
I was looking at the ubiquitin-proteasome system a few years ago. Essentially the function of the proteasome is to break down unwanted or damaged proteins inside the cell. Ubiquitin is used to tag proteins in the cell for destruction by the proteasome.

You might think that boosting the ubiquitin-proteasome system (UPS) would have an antiviral effect, but in fact it appears that you need to inhibit (or dysregulate) the UPS in order to reduce viral replication:

For coxsackievirus B:
Proteasome inhibition reduces coxsackievirus B3 replication in murine cardiomyocytes
Proteasome inhibition attenuates coxsackievirus-induced myocardial damage in mice
Dysregulation of the ubiquitin-proteasome system by curcumin suppresses coxsackievirus B3 replication

And for HIV:
The ubiquitin-proteasome system in HIV replication: potential targets for antiretroviral therapy

Although those above studies were on acute lytic coxsackievirus B infections; I am not sure if they will apply to the chronic intracellular non-cytolytic infections found in ME/CFS and chronic coxsackievirus B myocarditis.

I have not read of non-cytolytic viruses living inside pathogen-containing vacuoles.