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A Variety of Mouse PYHIN Proteins Restrict Murine and Human Retroviruses
Sümeyye Erdemci-Evin1, Matteo Bosso1, Veronika Krchlikova2
1Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany.
Abstract:
PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity.
Insights
PYHIN proteins are key mammalian immune sensors. This study shows many PYHIN proteins inhibit HIV-1 and MLV replication, highlighting their conserved role in innate antiviral immunity.
Area of Science:
- Immunology
- Virology
- Genetics
Background:
- PYHIN proteins are mammalian-specific immune effectors.
- Gene copy number of PYHIN proteins varies significantly across species.
- Emerging evidence suggests PYHIN proteins have direct antiviral mechanisms beyond cytosolic DNA sensing.
Purpose of the Study:
- To investigate the antiviral activity of all 13 murine PYHIN proteins against HIV-1 and MLV.
- To determine the correlation between PYHIN protein expression and retroviral inhibition.
- To explore the conserved role of PYHIN proteins in innate antiviral immunity.
Main Methods:
- Overexpression of individual murine PYHIN proteins.
- Assay of infectious HIV-1 production.
- Reporter gene assays using MLV-eGFP, HIV-1 LTR, and Friend MLV LTR constructs.
Main Results:
- Overexpression of specific PYHIN proteins (p203, p204, p205, p208, p209, p210, p211, p212) strongly inhibited HIV-1 production.
- Inhibitory effects correlated with suppression of reporter gene expression for MLV and HIV-1.
- PYHIN proteins p202, p207, and p213 showed no significant antiviral effect, while p206 and p214 had intermediate effects.
Conclusions:
- A subset of murine PYHIN proteins exhibit potent antiretroviral activity.
- The antiviral function of PYHIN proteins against retroviruses is conserved between humans and mice.
- Nuclear PYHIN proteins play a crucial role in innate antiviral immunity.
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