Resumen de Cpeb4 function in macrophages
As innate immune cells, macrophages sense endogenous and exogenous danger signals and respond orchestrating inflammatory processes. For the rapid induction and efficient resolution of inflammatory responses, macrophages induce the expression of proinflammatory and anti-inflammatory mediators, which cross-regulate each other through feedback loops. This process requires tightly controlled gene expression at multiple levels.
Recently, the regulation of mRNA deadenylation has emerged as a key regulator of the strength and, critically, the duration of transient inflammatory responses.
Cytoplasmic Polyadenylation Element Binding (CPEB1-4) family of RNA-binding proteins target mRNAs containing Cytoplasmic Polyadenylation Elements (CPEs) in their 3’UTR.
CPEBs orchestrate the assembly of two types of ribonucleoprotein complexes (mRNPs) which can repress or stimulate the translation of target mRNAs by modulating the length of poly(A) tail. Several inflammatory mediators harbour CPEs in their 3’UTRs and are potential CPEB targets. Thus, we hypothesized that CPEBs could be an additional checkpoint to control inflammatory responses.
We find that CPEB4 is a novel player in macrophage response to LPS. Upon LPS treatment, CPEB4 is upregulated and its polyadenylation function is activated, a process mediated by the MAPK p38α and ERK1/2 and two AU Rich Element Binding Proteins (ARE-BPs).
Interestingly, the pattern of CPEB4 expression and activity suggests that it participates in late LPS-response, when the resolution of inflammation occurs. Indeed, myeloid-specific Cpeb4KO mice display increased sensitivity to LPS-induced endotoxic shock. We identify CPEB4 target mRNAs by RNA-Immunoprecipitation and Sequencing (RIP-Seq), uncovering that CPEB4 regulates the expression of negative regulators of MAPK signalling, thus creating the negative feedback loop needed the resolution of inflammation. Moreover, we also describe how the interplay between CPEB4, HuR and TTP defines mRNA behaviour during the different temporal windows of inflammatory responses.
