Regulation of actin dynamics by protein kinase R control of gelsolin enforces basal innate immune defense.
Primary resistance to pathogens is reliant on both basal and inducible immune defenses. To date, research has focused upon inducible innate immune responses. In contrast to resistance via cytokine induction, basal defense mechanisms are less evident. Here we showed that the antiviral protein kinase R (PKR) inhibited the key actin-modifying protein gelsolin to regulate actin dynamics and control cytoskeletal cellular functions under homeostatic conditions. Through this mechanism, PKR controlled fundamental innate immune, actin-dependent processes that included membrane ruffling and particle engulfment. Accordingly, PKR counteracted viral entry into the cell. These findings identify a layer of host resistance, showing that the regulation of actin-modifying proteins during the innate immune response bolsters first-line defense against intracellular pathogens and has a sustained effect on virus production. Moreover, these data provide proof of principle for a concept in which the cell cytoskeleton could be targeted to elicit broad antiviral protection.
Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
Aaron T
AT
Irving
Die
D
Wang
Oliver
O
Vasilevski
Olivier
O
Latchoumanin
Noga
N
Kozer
Andrew H A
AH
Clayton
Anette
A
Szczepny
Hiroyuki
H
Morimoto
Dakang
D
Xu
Bryan R G
BR
Williams
Anthony J
AJ
Sadler
D000199:Actins / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003599:Cytoskeleton / Q000276:immunology / Q000378:metabolism; D018260:Gelsolin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008840:Microfilament Proteins / Q000276:immunology / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D014780:Viruses / Q000276:immunology / Q000378:metabolism; D019892:eIF-2 Kinase / Q000276:immunology / Q000378:metabolism*
D000199:Actins; D016207:Cytokines; D018260:Gelsolin; D008840:Microfilament Proteins; D019892:eIF-2 Kinase