A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

NF-κB and Extrinsic Cell Death Pathways - Entwined Do-or-Die Decisions for T cells.

NF-κB signaling is required at multiple stages of T cell development and function. The NF-κB pathway integrates signals from many receptors and involves diverse adapters and kinases. Recent advances demonstrate that kinases controlling NF-κB activation, such as the IKK complex, serve dual independent functions because they also control cell death checkpoints. Survival functions previously attributed to NF-κB are in fact mediated by these upstream kinases by novel mechanisms. This new understanding has led to a refined view of how NF-κB and cell death signaling are interlinked and how they regulate cell fate. We discuss how NF-κB activation and control of cell death signaling by common upstream triggers cooperate to regulate different aspects of T cell development and function.

IKK promotes naïve T cell survival by repressing RIPK1-dependent apoptosis and activating NF-κB.

The inhibitor of κB kinase (IKK) complex regulates the activation of the nuclear factor κB (NF-κB) family of transcription factors. In addition, IKK represses extrinsic cell death pathways dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by directly phosphorylating this kinase. Here, we showed that peripheral naïve T cells in mice required the continued expression of IKK1 and IKK2 for their survival; however, the loss of these cells was only partially prevented when extrinsic cell death pathways were blocked by either deleting Casp8 (which encodes the apoptosis-inducing caspase 8) or inhibiting the kinase activity of RIPK1. Inducible deletion of Rela (which encodes the NF-κB p65 subunit) in mature CD4+ T cells also resulted in loss of naïve CD4+ T cells and in reduced abundance of the interleukin-7 receptor (IL-7R) encoded by the NF-κB target Il7r, revealing an additional reliance upon NF-κB for the long-term survival of mature T cells. Together, these data indicate that the IKK-dependent survival of naïve CD4+ T cells depends on both repression of extrinsic cell death pathways and activation of an NF-κB-dependent survival program.

Prevalence of Borrelia burgdorferi and Borrelia miyamotoi in questing Ixodes ricinus ticks from four sites in the UK.

Borrelia miyamotoi is a spirochete bacterium related to Borrelia burgdorferi sensu lato, the cause of Lyme borreliosis, and vectored by ticks. In 2014, B. miyamotoi was identified in three questing Ixodes ricinus collected in the UK. We sought to confirm the presence of B. miyamotoi in the UK. Ticks were collected from four locations not previously investigated for B. miyamotoi or B. burgdorferi s.l. and of which two are considered as Lyme borreliosis "hotspots" based on hospital records of the disease. We independently confirm that B. miyamotoi is present in the UK and support the view that B. miyamotoi is likely to have a broad geographic distribution, at low levels. Our study also adds to the existing data on the distribution of B. burgdorferi s.l. in the UK and demonstrates that although the two "hotspots" had relatively high tick densities, they did not have the highest proportion of infected ticks.