NEMO Binds Ubiquitinated TANK-Binding Kinase 1 (TBK1) to Regulate Innate Immune Responses to RNA Viruses

RIG-I-like receptors (RLR) are intracellular sensors utilized by nearly all cell types for recognition of viral RNA, initiation of antiviral defense, and induction of type I interferons (IFN). TBK1 is a critical kinase implicated in RLR-dependent IFN transcription. Posttranslational modification of TBK1 by K63-linked ubiquitin is required for RLR driven signaling. However, the TBK1 ubiquitin acceptor sites and the function of ubiquitinated TBK1 in the signaling cascade are unknown. We now show that TBK1 is ubiquitinated on residues K69, K154, and K372 in response to infection with RNA virus. The K69 and K154 residues are critical for innate antiviral responses and IFN production. Ubiquitinated TBK1 recruits the downstream adaptor NEMO through ubiquitin binding domains. The assembly of the NEMO/TBK1 complex on the mitochondrial protein MAVS leads to activation of TBK1 kinase activity and phosphorylation of the transcription factor, interferon response factor 3. The combined results refine current views of RLR signaling, define the role of TBK1 polyubiquitination, and detail the mechanisms involved in signalosome assembly

Constitutional Adjudication and the ‘Dimensions’ of Judicial Activism: Comparative Legal and Institutional Heuristics

The dominant approach to constitutional law, and even more so to constitutional theory, has historically been judicial review-centred. Constitutional scholarship has often seemed ‘strong on positions and weak on analysis’, based on ‘foundationalist’/organic theories of judicial review, try- ing to justify or to reject the practice in toto and dictating its parameters. Behind such strong positions, and behind the search for ‘first-best principles’ of legitimacy, one can see a series of latent and intractable tensions, inherent in traditional constitutional theories of interpretation and adjudication: these tensions are the consequences of the unavoidably creative function of the judicial role. A pragmatic, second-best inquiry must probe the degree of such creativity, focusing on the questions of mode, limits, level of acceptability of law-making through the courts, and issues of institutional performance and systemic effects of adjudication. In light of all this, the paper will provide a taxonomy of the different types of criticisms that constitutional theories have raised regarding what we can broadly describe as the democratic legitimacy concerns of constitutional review. These are often lumped together, in different contexts, under the concept of ‘judicial activ- ism’, ranging from the very existence of judicial review, to the different forms of conceptualising the proper role of judicial interventions and the different modalities of constitutional adjudication. The paper will deal, in comparative perspective, with both American and Continental historical constitutional theories as well as the most recent trends of Institutional Analysis. The objective is to sketch a useful framework and some heuristic devices for the study of courts, different kinds of constitutional adjudication, and the spaces of discretion that are thereby implied