LPS induces KH-type splicing regulatory protein-dependent processing of microRNA-155 precursors in macrophages.
The importance of post-transcriptional mechanisms for the regulation of the homoeostasis of the immune system and the response to challenge by microorganisms is becoming increasingly appreciated. We investigated the contribution of microRNAs (miRNAs) to macrophage activation induced by lipopolysaccharide (LPS). We first observed that Dicer knockout in bone marrow-derived macrophages (BMDMs) increases the LPS-induced expression of some inflammation mediators. miRNA microarray analysis in BMDMs revealed that LPS significantly induces the expression of a single miRNA, miR-155, and this induction depends on enhanced miR-155 maturation from its precursors. The single-strand RNA-binding protein KH-type splicing regulatory protein (KSRP) binds to the terminal loop of miR-155 precursors and promotes their maturation. Both inhibition of miR-155 and KSRP knockdown enhance the LPS-induced expression of select inflammation mediators, and the effect of KSRP knockdown is reverted by mature miR-155. Our studies unveil the existence of an LPS-dependent post-transcriptional regulation of miR-155 biogenesis. Once induced, miR-155 finely tunes the expression of select inflammation mediators in response to LPS.
Ruggiero
Tina
T
RNA Technology Laboratory, Centro Biotecnologie Avanzate, Genoa, Italy.
Trabucchi
Michele
M
De Santa
Francesca
F
Zupo
Simona
S
Harfe
Brian D
BD
McManus
Michael T
MT
Rosenfeld
M Geoff
MG
Briata
Paola
P
Gherzi
Roberto
R
D000818:Animals; D053487:DEAD-box RNA Helicases / Q000172:deficiency; D004722:Endoribonucleases / Q000172:deficiency; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000378:metabolism*; D043244:Ribonuclease III; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
D018836:Inflammation Mediators; C507913:Khsrp protein, mouse; D008070:Lipopolysaccharides; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases