MicroRNA in autoimmunity and autoimmune diseases
Introduction
MicroRNAs (miRNAs) are 20–22 nucleotide long non-coding RNA molecules that were first discovered in 1993 [1], [2]. Currently, the known function of miRNAs is the post-transcriptional regulation of certain subsets of messenger RNAs (mRNAs) by binding to their 3′ untranslated region (UTR) thus targeting them for degradation or translational repression [3].
The importance of miRNA regulation to cellular functions is becoming increasingly clear as new miRNA targets are revealed. Currently, miRNA is known to regulate cellular processes such as apoptosis, differentiation, cell cycle, and immune functions. To date, the miRNA sequence database, miRBase, includes over 8000 predicted miRNAs in numerous species of plants, animals, and viruses [4], [5]. For humans alone, miRBase lists over 800 predicted miRNAs, and other bioinformatics predictions indicate that as much as one-third of all mRNAs may be regulated by miRNA [6].
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Biogenesis and maturation of miRNA
miRNAs are first transcribed from the genome by RNA polymerase II as primary miRNA (pri-miRNA) transcripts [7], [8]. In animals, miRNA maturation is then achieved by two main processing steps involving two ribonuclease III (RNase III) enzymes, Drosha and Dicer. First, Drosha and its partner protein DGCR8 (DiGeorge syndrome critical region 8) process the nuclear pri-miRNA into ∼70 nucleotide precursor miRNA (pre-miRNA) molecule [9], [10], [11], [12], [13]. The pre-miRNA is then exported from the
Cell biology and autoimmune targeting of the miRNA pathway
The key components of RISC are the argonaute (Ago) family of proteins. In mammals, there are four Ago proteins (Ago1–4), but only Ago2 is known to function in the miRNA and siRNA pathways. Ago2 has been shown to cleave mRNA targeted by miRNA or small interfering RNA (siRNA) and is known as the catalytic enzyme of RNA interference (RNAi) [22], [23]. In addition to Ago proteins, many other proteins are required for miRNA functioning including GW182 and Rck/p54, and these proteins all localize in
Role of miRNA in normal immune functions
Regulation of the immune system is vital to prevent many pathogenic disorders including autoimmune disease and cancers, and mammals have developed a complex system of checks and balances for immune regulation in order to maintain self tolerance while allowing immune responses to foreign pathogens, most of which are not fully understood. Recently, it has become evident that miRNAs play an important role in regulating immune response, as well as immune cell development. To date, a relatively
Role of miRNA in autoimmunity
Given that certain miRNA play critical roles in the regulation of immune response and immune cell development, it is not surprising that recent studies have revealed links between miRNA function and autoimmunity (Table 2). In 2007, the involvement of miRNA in a new pathway regulating autoimmunity was discovered in T lymphocytes in the sanroque mouse [54]. The sanroque mouse was originally selected from screening mutant mice derived from the chemical mutagen N-ethyl-N-nitrosourea (ENU), and has
Involvement of miRNA in autoimmune diseases
It is becoming increasingly clear from cell culture and animal studies that proper miRNA regulation is critical for the prevention of autoimmunity and normal immune functions. However, it is not yet well understood whether miRNA dysregulation could play a role in autoimmune disease pathogenesis in human patients. Several recent studies have uncovered possible roles for miRNA regulation in autoimmune diseases (Table 2), specifically rheumatoid arthritis (RA) and systemic lupus erythematosus
Acknowledgements
This work was supported in part by National Institute of Health grant AI47859 and the Andrew J. Semesco Foundation, Ocala FL. K.M.P. was supported by NIDCR oral biology training grant T32 DE007200.
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