TLR signals posttranscriptionally regulate the cytokine trafficking mediator sortilin.

Toshiki Yabe-Wada,Haifeng Shi,Mikita Suyama,Akira Nakamura,Shintaro Matsuba,Caroline C Philpott,Tetsuya Sato,Yasuyuki Ohkawa,Kazuya Takeda,Toshiyuki Takai

doi:10.1038/srep26566

Abstract

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.

Highlights

Ligands, and that sortilin plays a key role in cytokine production
B220+ splenocytes and bone marrow-derived plasmacytoid DCs and basophils showed lower expression levels of sortilin, while sortilin was hardly detected in bone marrow-derived mast cells (Fig. 1a). quantitative real time PCR (qRT-PCR) analysis revealed that sortilin was predominantly expressed in brain, lung and spleen, whereas lower expression of sortilin was observed in heart and liver (Fig. 1b)
We found that the C-rich elements (CREs)-containing sequence in the 3′ UTR of sortilin mRNA was amplified in the samples immunoprecipitated with anti-PCBP1 (Fig. 5c), indicating that PCBP1 can interact with the CRE in the 3′ UTR of endogenous sortilin mRNA

Summary

Introduction

Ligands, and that sortilin plays a key role in cytokine production. 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 important for the repression of excessive immune responses, such as chronic inflammation and autoimmune diseases[11]. 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 been identified[10,12]. 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. Our observations provide insights into the posttranslational regulation of cytokine production via the posttranscriptional control of sortilin expression

Methods

Results

Conclusion