Protein synthesis regulation, a pillar of strength for innate immunity? Rafael J Argu ¨ ello 1,2,3,5 , Christian Rodriguez Rodrigues 1,2,3,5 , Evelina Gatti 1,2,3,4,5 and Philippe Pierre 1,2,3,4,5 Recognition of pathogen derived molecules by Pattern Recognition Receptors (PRR) induces the production of cytokines (i.e. type I interferons) that stimulate the surrounding cells to transcribe and translate hundreds of genes, in order to prevent further infection and organize the immune response. Here, we report on the rising matter that metabolism sensing and gene expression control at the level of mRNA translation, allow swift responses that mobilize host defenses and coordinate innate responses to infection. Addresses 1 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Universite ´, U2M, 13288 Marseille, France 2 INSERM, U1104, 13288 Marseille, France 3 CNRS, UMR 7280, 13288 Marseille, France 4 Institute for Research in Biomedicine – iBiMED and Aveiro Health Sciences Program, University of Aveiro, 3810-193 Aveiro, Portugal Corresponding authors: Gatti, Evelina (gatti@ciml.univ-mrs.fr) and Pierre, Philippe (pierre@ciml.univ-mrs.fr) 5 These authors contributed equally to this work. Current Opinion in Immunology 2015, 32:28–35 This review comes from a themed issue on Innate immunity Edited by Zhijian J Chen and Sebastian Amigorena http://dx.doi.org/10.1016/j.coi.2014.12.001 0952-7915/# 2014 Elsevier Ltd. All rights reserved. Introduction Upon recognition of microbes locally, innate immune cells mount specific responses to control the infection from spreading to the entire organism. These responses consist mostly in the induction of cytokines and chemo- kines that impact the innate anti-microbial defenses in all the sites adjacent to the infection to allow the recruit- ment of effector cells adapted to the pathogen threat and capable of sterilizing and repairing the infected tissue. All these coordinated innate immune mechanisms take place in few hours after initial pathogen encounter and require profound changes in both mRNA and protein expression. Selective control of mRNA translation is thus emerging as a key mechanism for regulating synthesis of proteins that control, or are part of, the immune response to infection or pathogenic deregulation. Conversely, pathogenic bacteria and viruses have the capacity to interfere directly with ongoing host protein synthesis and can block innate responses. Here, we discuss novel advances on how pathogen recognition induces changes at the mRNA translational level that are essential to mount a specific and effective immune response to infection. Microbial patterns recognition and regulation of translation initiation Viral infection triggers in cells specific defense responses, through the production of type-I and type-III interferons (IFNs) [1]. IFNs induce, among hundred other antiviral genes, the expression of double-stranded (ds)RNA-de- pendent protein kinase (PKR) [2]. PKR activation by viral dsRNA promotes phosphorylation of a subunit of eukary- otic translation initiation factor 2 (p-eIF2a). This modifi- cation reduces the efficiency of translation initiation by eIF2a, due to the inhibition of GDP exchange for GTP, performed by the guanine nucleotide exchange factor 2B (eIF2B). The decrease in ternary complex levels (eIF2/ GTP/methionyl-tRNA) leads to a global translation shut off, and promote a specific transcriptional response that are believed to limit viral replication [3,4]. PKR is part of a larger family of kinases (eIF2Ks) that target eIF2a for phosphorylation upon cellular stress or viral infection, including the general control non-derepressible 2 (GCN2), that is normally activated by deacylated tRNAs upon amino acid starvation, but can also be stimulated by viral RNAs [5  ,6,7]. Productive viral infection can also lead to the accumulation of mal-conformed viral proteins in the endoplasmic reticulum (ER), which triggers an unfolded protein response (UPR), through the stimula- tion of PKR-like ER kinase (PERK) [8,9]. PERK activa- tion, like for other eIF2Ks, reduces considerably protein synthesis through eIF2a phosphorylation and interferes with productive viral replication, while promoting host cell apoptosis. Several genes present short upstream decoy open reading frames (uORFs) that prevent the efficient translation of the main ORF into a functional protein [10]. Upon eIF2a phosphorylation, reduced amounts of eIF2-GTP increase the probability of start codon readthrough of the decoy uORFs, and allow the downstream functional ORF to be translated. Typical examples of genes that use this strat- egy are ATF4 (Activating Transcription Factor 4), CHOP (C/EBP homologous protein), and GADD34 (growth Available online at www.sciencedirect.com ScienceDirect Current Opinion in Immunology 2015, 32:28–35 www.sciencedirect.com