TLRs Go Linear – On the Ubiquitin Edge

Toll-like receptors (TLRs) are crucial in protecting the host from pathogens. However, their exact role in disease remains incompletely understood. TLR signaling is tightly controlled because too little or too much TLR activation can result in immunodeficiency or autoinflammation, respectively. There is increasing evidence that linear ubiquitination, mediated by the linear ubiquitin chain assembly complex (LUBAC), plays a pivotal role in the regulation of TLR signaling. Recent advances have identified an intricate interaction between LUBAC and TLRs, with immunological consequences for infection and the development of autoinflammation in the host. We propose that defective linear ubiquitination contributes to TLR-mediated disease pathogenesis and that perturbed TLR signaling contributes to the phenotype observed in inherited LUBAC deficiency in humans and mice

Ubiquitin in the immune system

Ubiquitination is a post‐translational modification process that has been implicated in the regulation of innate and adaptive immune responses. There is increasing evidence that both ubiquitination and its reversal, deubiquitination, play crucial roles not only during the development of the immune system but also in the orchestration of an immune response by ensuring the proper functioning of the different cell types that constitute the immune system. Here, we provide an overview of the latest discoveries in this field and discuss how they impact our understanding of the ubiquitin system in host defence mechanisms as well as self‐tolerance

Scientific and local ecological knowledge, shaping perceptions towards protected areas and related ecosystem services

Context Most protected areas are managed based on objectives related to scientific ecological knowledge of species and ecosystems. However, a core principle of sustainability science is that understanding and including local ecological knowledge, perceptions of ecosystem service provision and landscape vulnerability will improve sustainability and resilience of social-ecological systems. Here, we take up these assumptions in the context of protected areas to provide insight on the effectiveness of nature protection goals, particularly in highly human-influenced landscapes. Objectives We examined how residents' ecological knowledge systems, comprised of both local and scientific, mediated the relationship between their characteristics and a set of variables that represented perceptions of ecosystem services, landscape change, human-nature relationships, and impacts. Methods We administered a face-to-face survey to local residents in the Sierra de Guadarrama protected areas, Spain. We used bi- and multi-variate analysis, including partial least squares path modeling to test our hypotheses. Results Ecological knowledge systems were highly correlated and were instrumental in predicting perceptions of water-related ecosystem services, landscape change, increasing outdoors activities, and human-nature relationships. Engagement with nature, socio-demographics, trip characteristics, and a rural-urban gradient explained a high degree of variation in ecological knowledge. Bundles of perceived ecosystem services and impacts, in relation to ecological knowledge, emerged as social representation on how residents relate to, understand, and perceive landscapes. Conclusions Our findings provide insight into the interactions between ecological knowledge systems and their role in shaping perceptions of local communities about protected areas. These results are expected to inform protected area management and landscape sustainability.Peer reviewe

Action needed for the EU Common Agricultural Policy to address sustainability challenges

Abstract Making agriculture sustainable is a global challenge. In the European Union (EU), the Common Agricultural Policy (CAP) is failing with respect to biodiversity, climate, soil, land degradation as well as socio-economic challenges. The European Commission's proposal for a CAP post-2020 provides a scope for enhanced sustainability. However, it also allows Member States to choose low-ambition implementation pathways. It therefore remains essential to address citizens' demands for sustainable agriculture and rectify systemic weaknesses in the CAP, using the full breadth of available scientific evidence and knowledge. Concerned about current attempts to dilute the environmental ambition of the future CAP, and the lack of concrete proposals for improving the CAP in the draft of the European Green Deal, we call on the European Parliament, Council and Commission to adopt 10 urgent action points for delivering sustainable food production, biodiversity conservation and climate mitigation. Knowledge is available to help moving towards evidence-based, sustainable European agriculture that can benefit people, nature and their joint futures. The statements made in this article have the broad support of the scientific community, as expressed by above 3,600 signatories to the preprint version of this manuscript. The list can be found here (https://doi.org/10.5281/zenodo.3685632). A free Plain Language Summary can be found within the Supporting Information of this article.Peer reviewe

LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

The linear ubiquitin chain assembly complex (LUBAC), composed of HOIP, HOIL-1 and SHARPIN, is required for optimal TNF-mediated gene activation and to prevent cell death induced by TNF. Here, we demonstrate that keratinocyte-specific deletion of HOIP or HOIL-1 (E-KO) results in severe dermatitis causing postnatal lethality. We provide genetic and pharmacological evidence that the postnatal lethal dermatitis in HoipE-KO and Hoil-1E-KO mice is caused by TNFR1-induced, caspase-8-mediated apoptosis that occurs independently of the kinase activity of RIPK1. In the absence of TNFR1, however, dermatitis develops in adulthood, triggered by RIPK1-kinase-activity-dependent apoptosis and necroptosis. Strikingly, TRAIL or CD95L can redundantly induce this disease-causing cell death, as combined loss of their respective receptors is required to prevent TNFR1-independent dermatitis. These findings may have implications for the treatment of patients with mutations that perturb linear ubiquitination and potentially also for patients with inflammation-associated disorders that are refractory to inhibition of TNF alone

The activity of TRAF RING homo- and heterodimers is regulated by zinc finger 1

Ubiquitin chains linked through lysine63 (K63) play a critical role in inflammatory signalling. Following ligand engagement of immune receptors, the RING E3 ligase TRAF6 builds K63-linked chains together with the heterodimeric E2 enzyme Ubc13-Uev1A. Dimerisation of the TRAF6 RING domain is essential for the assembly of K63-linked ubiquitin chains. Here, we show that TRAF6 RING dimers form a catalytic complex where one RING interacts with a Ubc13~Ubiquitin conjugate, while the zinc finger 1 (ZF1) domain and linker-helix of the opposing monomer contact ubiquitin. The RING dimer interface is conserved across TRAFs and we also show that TRAF5–TRAF6 heterodimers form. Importantly, TRAF5 can provide ZF1, enabling ubiquitin transfer from a TRAF6-bound Ubc13 conjugate. Our study explains the dependence of activity on TRAF RING dimers, and suggests that both homo- and heterodimers mediated by TRAF RING domains have the capacity to synthesise ubiquitin chains