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.
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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)