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Review
. 2021 Aug 7;10(8):2020.
doi: 10.3390/cells10082020.

The Role of microRNAs in NK Cell Development and Function

Arash Nanbakhsh  1 , Subramaniam Malarkannan  1   2   3   4
Affiliations
Review

The Role of microRNAs in NK Cell Development and Function

Arash Nanbakhsh et al. Cells. .

Abstract

The clinical use of natural killer (NK) cells is at the forefront of cellular therapy. NK cells possess exceptional antitumor cytotoxic potentials and can generate significant levels of proinflammatory cytokines. Multiple genetic manipulations are being tested to augment the anti-tumor functions of NK cells. One such method involves identifying and altering microRNAs (miRNAs) that play essential roles in the development and effector functions of NK cells. Unique miRNAs can bind and inactivate mRNAs that code for cytotoxic proteins. MicroRNAs, such as the members of the Mirc11 cistron, downmodulate ubiquitin ligases that are central to the activation of the obligatory transcription factors responsible for the production of inflammatory cytokines. These studies reveal potential opportunities to post-translationally enhance the effector functions of human NK cells while reducing unwanted outcomes. Here, we summarize the recent advances made on miRNAs in murine and human NK cells and their relevance to NK cell development and functions.

Keywords: Mirc11; NK cells; inflammation; microRNAs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Biogenesis of miRNAs. The non-coding miRNAs are transcribed as Pri-miRNAs. This is processed by a complex containing Drosha and DiGeorge syndrome critical region 8 (DGCR8) within the nucleus to generate precursor-miRNA (Pre-miRNA). Pre-miRNAs are exported to the cytoplasm via exportin-5 that is located in the nuclear membrane. The 7-methylguanine-capped (m7G) pre-miRNAs depend on Dicer to complete their cytoplasmic maturation. The miRNA-induced silencing complex (RISC) recruits miRNA and the target transcripts to induce specific translational repression.
Figure 2
Figure 2
MicroRNAs regulate murine and human NK cell development and functions. Several microRNAs play an essential role in positively or negatively regulating the NK cell ontogeny. (A) Lineage commitment of progenitors to NKPs is regulated by miR-181a and miR-181b that target the transcript encoding NLK, a negative regulator of Notch signaling. (B) Early development and terminal maturation of NK cells are regulated by several miRNAs. The primary target of these miRNAs is the transcripts of transcription factors, including Eomes and Tbx21. (C) MicroRNA miR-146a targets transcripts encoding KIR2DL and TRAF6. KIRs interact with self MHC Class I and thereby determine the threshold of activation and licensing during the terminal maturation of NK cells. (D) MicroRNAs regulate the effector functions of NK cells. These regulatory effects occur at three levels: (1) miR-155 degrades the transcript encoding lipid phosphatase SHIP that converts PI(3,4,5)P3 into PI(3,4)P2; conversely, an increase in the concentration of PIP3 augments the overall activation of NK cells; (2) miR-29 and miR-150 target messages encoding transcription factors, including Eomes, Tbx21, and c-Myb; (3) several microRNAs target the transcripts encoding effector molecules perforin, granzyme-b, and interferon gamma.
Figure 3
Figure 3
Mirc11 family is evolutionarily conserved. (A) Mirc11 cistron (miRNA-23a cluster) is a tri-miRNA cluster. It consists of three members, miR-23a, miR-27a, and miR-24-2, which are derived from a single primary mRNA transcript. The highlighted region forms the ‘seed sequences’ of these microRNAs. (B) Mirc11 cistron is highly conserved in mouse, rat, horse, dog, and human genomes.
Figure 4
Figure 4
Members of the Mirc11 family target multiple transcripts. Members of the Mirc11 cistron miR-23a (A), miR-24-2 (B), and miR-27a (C) have the potentials to silence the translation of hundreds of mRNAs by targeting unique ‘seed’ sequences present in their 3′-UTR. Using TargetScan 7.1-based in silico analyses (http://www.targetscan.org, accessed on 28 July 2021), potential target transcripts in the total genome-wide RNA sequencing data were identified from NK cells based on ‘the aggregate probability of conserved targeting’ (PCT). The ENCODE Data Coordination Center portal-based whole-genome alignments were used to determine the transcripts that are the targets of Mirc11 family members. A select few target transcripts of the Mirc11 cistron are shown.
Figure 5
Figure 5
Mirc11 targets members of E3 ligases. The 3′-UTR of the transcripts encoding E3 ligases A20 (TNFAIP3), Cblb, Itch, Cyld contains target sequences for the members of the Mirc11 cluster. (A) The 3′UTR of Tnfaip3 contained one seed match for miRNA23a-3p at 1664–1671 nts. (B) The 3′-UTR of Cblb contained two seed matches at 3216–3236 and 5879–5901 nts targeted by miR-27a-3p and miR-23a-3p, respectively. However, the role of miR-27a-3p and miR-23a-3p in degrading the Cblb transcript has not been established. (C) The 3′-UTR of Cyld contained three sequences at 3842–3864, 4031–4051, and 5979–6000 nts, which were all targeted by miR-24-2-3p. (D) The 3′-UTR of Itch contained two seed matches at 2882–2900 and 4649–4669 nts that were targeted by miR-27a-3p and miR-23a-3p, respectively.
Figure 6
Figure 6
Mirc11 and inflammation. Members of the Mirc11 family function as cytoplasmic checkpoints to downregulate the functions of ubiquitin modifiers and augment translation of the transcripts encoding inflammatory cytokines. Signaling from activation receptors propagate by recruiting membrane-proximal Src kinase Fyn and scaffold protein ADAP. Functions of the ADAP include the assembly of the Carma1-Bcl10-Malt1 (CBM) signalosome. TRAF6 is one of the major ubiquitin E3 ligases in lymphocytes and auto-ubiquitylates K63 moieties of ubiquitin. K63-linked polyubiquitin functions as a scaffold in recruiting downstream effectors, including Tak1 involved in activating AP1 via Jnk1/2, p38, c-Jun. Tak1 also recruits Tab1, Tab2, and Tab3. K63 ubiquitylation of Tab2 allows the recruitment of Rip1 or Nemo and the eventual activation of NF-κB. Ubiquitin modifiers (Itch) and deacetylases (A20, Cyld) are involved in negatively regulating the functions of TRAF6 and Tabs. They achieve this by actively removing the K63 ubiquitin moieties and by adding K48-linked ubiquitin that marks proteins for proteasome-based degradation. Mirc11 family members target Cyld, A20, and Itch. Using ‘seed sequences’, members of the Mirc11 family target sequences in the 3′ end of the transcripts; these microRNAs can function as the positive regulators of NF-κB and AP1 transcription factors.
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