Regulation of innate immunity by Nrf2.

The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been mainly investigated as a regulator of redox homeostasis. However, research over the past years has implicated Nrf2 as an important regulator of innate immunity. Here, we discuss the role of Nrf2 in the innate immune response, highlighting the interaction between Nrf2 and major components of the innate immune system. Indeed, Nrf2 has been shown to widely control the immune response by interacting directly or indirectly with important innate immune components, including the toll-like receptors-Nuclear factor kappa B (NF-kB) pathway, inflammasome signaling, and the type-I interferon response. This indicates an essential role for Nrf2 in diseases related to microbial infections, inflammation, and cancer. Yet, further studies are required to determine the exact mechanism underpinning the interactions between Nrf2 and innate immune players in order to allow a better understanding of these diseases and leverage new therapeutic strategies.

Lysyl-tRNA synthetase produces diadenosine tetraphosphate to curb STING-dependent inflammation.

Inflammation is an essential part of immunity against pathogens and tumors but can promote disease if not tightly regulated. Self and non-self-nucleic acids can trigger inflammation, through recognition by the cyclic GMP-AMP (cGAMP) synthetase (cGAS) and subsequent activation of the stimulator of interferon genes (STING) protein. Here, we show that RNA:DNA hybrids can be detected by cGAS and that the Lysyl-tRNA synthetase (LysRS) inhibits STING activation through two complementary mechanisms. First, LysRS interacts with RNA:DNA hybrids, delaying recognition by cGAS and impeding cGAMP production. Second, RNA:DNA hybrids stimulate LysRS-dependent production of diadenosine tetraphosphate (Ap4A) that in turn attenuates STING-dependent signaling. We propose a model whereby these mechanisms cooperate to buffer STING activation. Consequently, modulation of the LysRS-Ap4A axis in vitro or in vivo interferes with inflammatory responses. Thus, altogether, we establish LysRS and Ap4A as pharmacological targets to control STING signaling and treat inflammatory diseases.

[Effect of regulator protein Nef on the viral activity of human immunodeficiency virus]. / Effet de la protéine régulatrice Nef sur le pouvoir infectieux du virus de l'immunodéficience humaine.

Despite 25 years of research on human immunodeficiency virus (HIV), the functions of some viral proteins are not fully understood. The role of Nef in the evolution of HIV-1 infection towards immunodeficiency is undeniable; however, the mechanisms involved in this function of Nef remain elusive. The interaction of Nef with a large number of cellular partners disrupts the metabolism of infected cells, including the endocytic pathway, in favor of viral spread. Down-regulation of cell-surface major histocompatibility complex (MHC) molecules by Nef enables infected cells to escape immune surveillance. Nef-induced down-regulation of CD4 increases the infectivity of virions by increasing the incorporation of the envelope glycoproteins into the viral membrane. In addition, Nef increases viral infectivity through a mechanism that is independent of MHC and CD4 down-regulation that nonetheless requires the ability of Nef to interfere with the endocytic process. Overall, these properties promote viral spread in the infected host.