Cellular Protein Kinase D Modulators Play a Role during Multiple Steps of Herpes Simplex Virus 1 Egress

Area of Science:

• Virology
• Cell Biology
• Molecular Biology

Background:

• Herpes simplex virus 1 (HSV-1) assembly occurs in the nucleus, followed by transport across nuclear membranes and final envelopment.
• The host protein kinase D (PKD) and diacylglycerol are known to promote HSV-1 release from the trans-Golgi network (TGN).
• The precise contribution of host cell machinery to viral release, particularly during non-synchronized infections, remains incompletely understood.

Purpose of the Study:

• To investigate the role of the protein kinase D (PKD) pathway in herpes simplex virus 1 (HSV-1) egress during non-synchronized infections.
• To determine how various regulators of PKD influence viral production and release.
• To explore potential novel roles of PKD in different stages of the HSV-1 life cycle.

Main Methods:

• RNA interference was used to target and inhibit various protein kinase D (PKD) regulators.
• Viral production and extracellular release were monitored following the inhibition of PKD regulators.
• Overexpression studies, pharmacological treatments, and lipid assays were employed to investigate the mechanisms involved.
• Electron microscopy was utilized to map viral intermediates and identify specific stages of egress affected.

Main Results:

• Targeting several protein kinase D (PKD) regulators negatively impacted the extracellular release of herpes simplex virus 1 (HSV-1).
• These effects on viral release were largely independent of total intracellular diacylglycerol levels.
• Electron microscopy revealed that some PKD modulators influence distinct steps in viral egress, including nuclear egress.

Conclusions:

• The protein kinase D (PKD) pathway plays a more complex role in herpes simplex virus 1 (HSV-1) egress than previously anticipated.
• PKD machinery appears to modulate not only late-stage release but also earlier events like nuclear egress.
• These findings open new avenues for research into controlling HSV-1 infection by targeting the PKD pathway.