The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a wellestablished inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis

Let's hear it from the cities:On the role of renewable energy in reaching climate neutrality in urban Europe

Renewable energy sources have emerged globally as a key lever to ensure energy security and to promote climate mitigation. Cities need to exploit this energy transition, but how they are building their strategies and actions is undetermined. A new dataset, collected through the European 100 Climate-Neutral and Smart Cities Mission, offers unique insights on the 362 cities which expressed the ambition to reach climate neutrality by 2030. Insights include their level of preparedness, ambition, capacity and the risks envisaged in the pursuit of zero-emission and greener futures. This study focuses in particular on the role of renewable energy across high greenhouse gas emitting sectors in cities (e.g. buildings, mobility, waste and industry). It analyses i) the status quo for renewable energy generation, consumption, and policymaking, ii) the key measures to enhance and upscale renewable energy deployment in the near future, and iii) how policies and relevant instruments will evolve to curb emissions and accelerate the energy transition. The insights that emerge from the analysis are discussed in relation to existing evidence, to inform future research strands and forms of assistance for cities. Overall, for cities to deliver on large renewable projects, efforts need to be intensified, barriers need to be lifted and multi-governance approaches must be operationalised.</p

Canonical IRE1 function needed to sustain vigorous natural killer cell proliferation during viral infection

The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency of IRE1 and its downstream transcription factor XBP1 in NKp46+ NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1-sufficient Ly49H+ NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that IRE1/XBP1 activation is required during vigorous NK cell proliferation early upon viral infection, as part of a canonical UPR response.</p