Abstract
SummaryProtein fatty acylation regulates diverse aspects of cellular function and organization and plays a key role in host immune responses to infection. Acylation also modulates the function and localization of virus-encoded proteins. Here, we employ chemical proteomics tools, bio-orthogonal probes, and capture reagents to study myristoylation and palmitoylation during infection with herpes simplex virus (HSV). Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed. Furthermore, we found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases. Taken together, our results provide broad oversight of protein acylation during HSV infection, a roadmap for similar analysis in other systems, and a resource with which to pursue specific analysis of systems and functions.
Highlights
Covalent modification of proteins by saturated fatty acids represents a critical regulatory mechanism in processes including membrane and microdomain targeting, vesicular transport, signaling, cell structure, metabolic pathways, neurotransmission, infection, and immunity (Aicart-Ramos et al, 2011; Bijlmakers, 2009; Iwanaga et al, 2009; Resh, 2012)
Using in-gel fluorescence imaging and quantitative mass spectrometry, we demonstrate a generalized reduction in myristoylation of host proteins, whereas palmitoylation of host proteins, including regulators of interferon and tetraspanin family proteins, was selectively repressed
We found that a significant fraction of the viral proteome undergoes palmitoylation; we identified a number of virus membrane glycoproteins, structural proteins, and kinases
Summary
Covalent modification of proteins by saturated fatty acids represents a critical regulatory mechanism in processes including membrane and microdomain targeting, vesicular transport, signaling, cell structure, metabolic pathways, neurotransmission, infection, and immunity (Aicart-Ramos et al, 2011; Bijlmakers, 2009; Iwanaga et al, 2009; Resh, 2012). In the herpesviruses UL11, a conserved and essential structural protein, is subject to both myristoylation and palmitoylation, modifications that are essential for normal membrane association (Loomis et al, 2001; MacLean et al, 1989) Both human cytomegalovirus and Epstein-Barr virus encode homologs of UL11 (UL99 and BBLF1, respectively), which have been shown to be lipidated; the precise nature of the lipidation in relation to virus assembly remains to be determined, but these proteins are all required for virus replication (Chiu et al, 2012; Sanchez et al, 2000). It has been reported that another herpes simplex virus (HSV) tegument protein, UL51, undergoes palmitoylation, the importance of this modification has not been studied in detail (Nozawa et al, 2003) From these and other examples, it is clear that covalent modification of host- and virus-encoded proteins plays important roles in many aspects of virus-host interaction including entry, assembly, and immune responses
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