Regulation of IRF7 through cell type-specific protein stability.
Interferon regulatory factor 7 (IRF7) is a key component of the cellular response to virus infection that culminates in physiologically relevant IFNalpha production. We studied molecular mechanisms governing responses to respiratory viral infection that are characterized by transient induction and subsequent shut-off of interferon (IFN) gene expression. We asked whether alterations in IRF7 protein stability occurred during virus infection that might contribute to this regulation. To this end, we measured IRF7 half-life in various cell types and found it to be short-lived, in marked contrast to the pronounced stability of the related transcription factor, IRF3. Furthermore, virus infection accelerated IRF7 degradation in a proteosome-dependent manner in most cell types. However, plasmacytoid dendritic cells (pDC), which constitute the major circulating IFN producing cell type, displayed a distinct pattern of regulation. Infection of lymphoid tissues, where the majority of IRF7 is expressed in pDC, attenuated the normal proteosome-mediated degradation of IRF7, resulting in a long-lived protein. Stabilization was partially stimulated by autocrine IFN as a positive feedback mechanism, but was partially IFN independent. Thus, two distinct posttranslational mechanisms regulate IRF7 activity in response to viral infection, with protein turnover attenuating responses postinfection in most cell types while infection-induced protein stabilization contributes to the heightened IFN production characteristic of pDC.
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 1(st) Ave MSB548, New York, NY 10016, USA.
Arun
A
Prakash
David E
DE
Levy
D000818:Animals; D002478:Cells, Cultured; D006207:Half-Life; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000494:pharmacology; D051379:Mice; D009928:Organ Specificity; D011489:Protein Denaturation; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494233:Irf3 protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse