Physiological roles of miR-155

Abstract

miR-155 is involved in non-coding microRNAs found in humans, mice and chickens of which the sequence is conserved. Historically, miR-155 was identified as a B-cell integration cluster (bic), which induces B-cell leucosis in chickens, by its activation through viral promoter insertion. Subsequent studies have shown that transgenic mice expressing miR-155 in B cells generated lymphoma, showing that miR-155 is oncogenic. Biochemical investigation identifies many substrates of miR-155, and one of them in B cells and macrophages is the SH2-domain containing inositol-5'-phosphatase 1. A deficiency of miR-155 in the immune system causes attenuated immune functions. Clinically, several types of malignancy including diffuse large B-cell lymphoma have high miR-155 expression levels.

Keywords: SH2-domain containing inositol-5′-phosphatase 1; inflammation; microRNA; signal transduction; tyrosine kinase.

Figure 1

Biotransformation of microRNAs (miRNAs). First, precursor miRNA is transcribed by RNA polymerase II from DNA in the nucleus, followed by hydrolysis by an RNase III enzyme Drosha to form multiple hairpin-shaped pre-miRNAs. The generated pre-miRNA is transported into the cytosol by a nuclear membrane protein exportin-5. Subsequently, the loop structure in the hairpin RNA is cleaved by another RNase III enzyme Dicer. This reaction results in a duplexed RNA that is incorporated into an RNA-induced silencing complex (RISC) constituted with Argonaute protein to form an miRISC. Finally, mRNA to be processed is incorporated in this protein–RNA machinery.

Figure 2

Comparison of target sequences in mammalian genes and the seed sequence of miR-155. (a) Human, mouse and chicken miR-155 seed sequences. The Kaposi sarcoma-associated herpesvirus (KSHV) -derived miR-K12-11 seed sequence is also shown. (b) Complementarity of the target sequences of human SHIP1 3′-UTR and the seed sequence of human miR-155. (c) Target sequences of PU.1, C/EBPβ, SOCS1, and Jarid2 in mice and humans. C/EBPβ, CCAAT/enhancer-binding protein beta; Jarid2, jumonji, AT rich interactive domain 2; PU.1, transcription factor that binds to the PU-box, a purine-rich DNA sequence; SOCS1, suppressor of cytokine signalling 1; UTR, untranslated region.

Figure 3

Activation of a B-cell and its regulation by miR-155. When B-cell receptor is activated by the F(ab')₂ of antibody in general, a cytoplasmic protein tyrosine kinase Lyn activates a downstream tyrosine kinase Syk, followed by the initiation of the ITAM-mediated signalling pathway. When B cells are activated by the whole molecule of antibody, but not by F(ab')₂, the activated Lyn phosphorylates Syk as well as ITIM in the cytoplasmic region of FcγRIIB. Tyrosine-phosphorylated ITIM then recruits SHIP1 as well as other negative regulators, leading to cell inactivation. miR-155 impairs SHIP1 expression, leading to enhanced B-cell activation in response to the whole molecule of antibody. Note that an intact antibody in general can be cleaved by pepsin protease into an F(ab')₂ fragment and an Fc fragment. ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif.

Figure 4

Mode of action of Jarid2 on il22 expression and its regulation by miR-155. Under basal conditions, the transcription of il22 occurs normally in response to physiological stimuli (upper). In the absence of miR-155, when Jarid2 expression increases, the recruitment of PRC2 complex including Suz12 occurs. The formed PRC2 induces H3K27 methylation in the il22 locus, leading to its inactivation (lower).