TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin

Scientific Reports, May 2016

Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN-α, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-α secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-α in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3′ UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.nature.com/articles/srep26566.pdf

TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin

TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin ToshikiYabe-Wada Shintaro Matsuba Kazuya Takeda Tetsuya Sato Mikita Suyama Yasuyuki Ohkawa Toshiyuki Takai Haifeng Shi Caroline C. Philpott Akira Nakamura OPEN Regulating the transcription, translation and secretion of cytokines is crucial for controlling the appropriate balance of inflammation. Here we report that the sorting receptor sortilin plays a key role in cytokine production. We observed interactions of sortilin with multiple cytokines including IFN?, and sortilin depletion in plasmacytoid dendritic cells (pDCs) led to a reduction of IFN-? secretion, suggesting a pivotal role of sortilin in the exocytic trafficking of IFN-? in pDCs. Moreover, sortilin mRNA was degraded posttranscriptionally upon stimulation with various TLR ligands. Poly-rC-binding protein 1 (PCBP1) recognized the C-rich element (CRE) in the 3? UTR of sortilin mRNA, and depletion of PCBP1 enhanced the degradation of sortilin transcripts, suggesting that PCBP1 can act as a trans-acting factor to stabilize sortilin transcripts. The nucleotide-binding ability of PCBP1 was impaired by zinc ions and alterations of intracellular zinc affect sortilin expression. PCBP1 may therefore control the stability of sortilin transcripts by sensing intracellular zinc levels. Collectively, our findings provide insights into the posttranslational regulation of cytokine production through the posttranscriptional control of sortilin expression by TLR signals. - Infection by various pathogens and subsequent cellular stimuli leads to rapid inflammatory responses through a set of pattern-recognition receptors (PRRs) that includes Toll-like receptors (TLRs), helicase RIG-I?like receptors and biosensor Nod?like receptors1. The PRR signals induce production of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 6 (IL-6), as well as type I interferons (IFNs) and chemokines, and type I IFNs and cytokines are involved in the inflammation process. Excessive immune responses are defined by overproduction of cytokines and contribute to tissue damage by chronic inflammation as well as the development of autoimmune diseases. Therefore, it is imperative to maintain cytokines at resting-state levels by tight control of the signaling pathways that govern cytokine production. Regulating the secretion of cytokines from immune cells, as well as their expression, is important for the suppression of excessive immune responses. Although many studies have elucidated the molecular details of signaling pathways for cytokine production1, we know little about the mechanisms of cytokine secretion from immune cells2. Sortilin is a type 1 membrane protein and is evolutionarily conserved from yeast to humans3. It is a multifunctional receptor that binds many kinds of ligands, and thus exerts diverse cellular functions such as lipoprotein metabolism and insulin-regulated glucose uptake3?6. Sortilin is predominantly found in early endosomes and in the trans-Golgi network7, and its localization is regulated by cargo adaptor complexes3. Recent studies have demonstrated that loss of sortilin impairs the secretion of IL-6 and IFN-? cytokines in macrophages and T cells8,9. Interestingly, surface plasmon resonance (SPR) analysis and immunofluorescence microscopy have indicated a physiological interaction between sortilin and IL-6 and IFN-?8,9, and sortilin deficiency in immune cells leads to the attenuation of inflammation and atherosclerosis8. These observations indicate that IL-6 and IFN-? are sortilin ligands, and that sortilin plays a key role in cytokine production. However, it remains unclear whether sortilin is able to recognize other immune cytokines, and how its expression is regulated upon stimulation in immune cells. Recent research has demonstrated that trans-acting factors such as RNA-binding proteins (RBPs) play a key role in the posttranscriptional regulation of immunity-related mRNAs10, and this regulation is also important for the repression of excessive immune responses, such as chronic inflammation and autoimmune diseases11. Specific cis-elements in the 3? UTR, such as AU-rich elements (AREs) and stem-loop structures, are possessed by many immunity-related mRNAs and contribute to their degradation or stabilization, and various trans-acting factors involved in this regulation have also been identified10,12. Tristetraprolin, AUF1 and HuR are ARE-binding proteins that control the stability of mRNAs containing AREs, and stem-loop structures are recognized by Roquin and Regnase-1 followed by destabilization of target mRNAs10?12. The functions of these trans-acting factors are regulated by a number of kinase pathways, resulting in the coordinated expression of their target mRNAs10,11. Poly-rC-binding protein (PCBP) 1 (also called hnRNP E1, or alpha-CP-1) is a multifunctional RBP that recognizes C-rich elements (CREs) of single-stranded RNA and has diverse funct (...truncated)


This is a preview of a remote PDF: https://www.nature.com/articles/srep26566.pdf

Toshiki Yabe-Wada, Shintaro Matsuba, Kazuya Takeda, Tetsuya Sato, Mikita Suyama, Yasuyuki Ohkawa, Toshiyuki Takai, Haifeng Shi, Caroline C. Philpott, Akira Nakamura. TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin, Scientific Reports, 2016, Issue: 6, DOI: 10.1038/srep26566