A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance

Abstract

Patients carrying very rare loss‐of‐function mutations in interleukin‐1 receptor–associated kinase 4 (IRAK4), a critical signaling mediator in Toll‐like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon‐alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll‐like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor–associated factor 6, a vital step in signal transduction. Conclusion: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity. (Hepatology 2015;62:1375–1387)

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

“…ASC, NLRP3 and BTK coding sequences in pENTR clones were generated as described in ( 18) . Truncated Flag-tagged NLRP3 constructs were a kind gift of F. Martinon, Lausanne, Switzerland ( 15) .…”

Human NACHT, LRR, and PYD domain–containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase

“…ASC, NLRP3, and BTK coding sequences in pENTR clones were generated, as described by Wang et al 18 and in the Methods section in this article's Online Repository.…”

“…mRNA was isolated with the RNeasy Mini Kit on a Qiacube robot (both from Qiagen, Hilden, Germany) and transcribed to cDNA (High Capacity RNA-to-cDNA Kit; Life Technologies), and Il1b, Nlrp3, IL1B, and NLRP3 mRNA expression was quantified in triplicates relative to TATAA-box binding protein (Tbp/TBP) by using TaqMan primers (Life Technologies) on a realtime cycler (7500 fast; Applied Biosystems, Foster City, Calif), as described by Wang et al 18 Comparable cycle threshold values for TBP (data not shown) in all treatment groups confirmed equal cell numbers.…”

Hepatitis C Virus Infection Induces Hepatic Expression of NF-κB-Inducing Kinase and Lipogenesis by Downregulating miR-122

“…Thus, NIK, a central regulatory kinase for IKK-␣ activation, plays an important role in the IKK-␣-mediated effects on HCV assembly and lipogenic induction. Interestingly, in a recent signalome-wide study, the canonical NF-B pathway was found to restrict HCV infection, while silencing of IRAK2 or NIK of the noncanonical NF-B pathway reduced viral replication (25), thus supporting a proviral role of NIK in HCV infection.…”