Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation

Abstract

N 6-methyladenosine (m6A) is the most prevalent modification in eukaryotic messenger RNAs (mRNAs) and is interpreted by its readers, such as YTH domain-containing proteins, to regulate mRNA fate. Here we report the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1/2/3) as a distinct family of m6A readers that target thousands of mRNA transcripts through recognizing the consensus GG(m6A)C sequence. In contrast to the mRNA-decay-promoting function of YTHDF2, IGF2BPs promote the stability and storage of their target mRNAs (e.g., MYC) in an m6A-depedent manner under normal and stress conditions and thus affect gene expression output. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A and are critical for their oncogenic functions. Our work therefore reveals a different facet of the m6A-reading process that promotes mRNA stability and translation, and highlights the functional importance of IGF2BPs as m6A readers in post-transcriptional gene regulation and cancer biology.

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

“…Yet numerous studies have shown that the m 6 A modification of mRNA effects nearly every step in its life cycle, and the resulting effect on m 6 A-modified mRNA depends on the specific YTH domain family reader protein that binds to the mRNA (77). Further complicating the fate of m 6 A-modified mRNA is the recent discovery that insulin-like growth factor-2 mRNAbinding proteins (IGFBP1-3) also bind to m 6 Acontaining transcripts, and have the opposite effect as YTHDF2, resulting in stabilization of mRNA (78). Taken together, this means that we are unable to speculate what effect reducing m 6 A marks has on the mRNAs affected in Gsk-3 DKO ESCs.…”

RNA m6A modification and its function in diseases

“…In their study, IGF2BPs recognized the consensus GG(m 6 A)C sequence of mRNA targets through their K homology domains. Interestingly, in contrast to YTHDF2, which promoted the decay of target mRNAs, IGF2BPs promoted the translation of target mRNAs (MYC, for example) by increasing their stability and storage [59]. The findings of m 6 A readers with distinct regulatory functions suggested the diversity of m 6 A functions.…”

“…However, the mechanism of how IGF2BPs function was obscure. Huang et al [59] reidentified IGF2BPs as a new class of m 6 A readers by m 6 A RNA bait pulldown experiment combined with a computational screening of m 6 A-binding proteins. In their study, IGF2BPs recognized the consensus GG(m 6 A)C sequence of mRNA targets through their K homology domains.…”

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP 1/ IGF 2 BP 1

“…Photoactivatable ribonucleoside‐enhanced crosslinking and immunoprecipitation (PAR‐CLIP) and enhanced crosslinking and immunoprecipitation (eCLIP) studies have identified a myriad of IMP1 targets, providing important insight into the diverse roles of IMP1 via regulation of specific transcripts . Finally, recent reports suggest that IMP proteins are “readers” of N 6‐methyladenosine (m 6 A) modified mRNAs, which may impart binding and functional specificity of IMPs to regulate mRNA storage and stability .…”