MBNL expression in autoregulatory feedback loops

Abstract

Muscleblind-like (MBNL) proteins bind to hundreds of pre- and mature mRNAs to regulate their alternative splicing, alternative polyadenylation, stability and subcellular localization. Once MBNLs are withheld from transcript regulation, cellular machineries generate products inapt for precise embryonal/adult developmental tasks and myotonic dystrophy, a devastating multi-systemic genetic disorder, develops. We have recently demonstrated that all three MBNL paralogs are capable of fine-tuning cellular content of one of the three MBNL paralogs, MBNL1, by binding to the first coding exon (e1) of its pre-mRNA. Intriguingly, this autoregulatory feedback loop grounded on alternative splicing of e1 appears to play a crucial role in delaying the onset of myotonic dystrophy. Here, we describe this process in the context of other autoregulatory and regulatory loops that maintain the content and diverse functions of MBNL proteins at optimal level in health and disease, thus supporting the overall cellular homeostasis.

Loss of function of the RNA export factor,Nxt1, inDrosophilacauses muscle degeneration and reduced expression of genes with long introns

“…The production of the mbl circRNA is regulated by Mbl protein itself, in an autoregulatory feedback loop. In vertebrates it appears that MBNL1 does not regulate production of its own circRNA in neuronal cells, but the effect in muscle has not been determined [19,45]. Our discovery that defects in an RNA export factor, Nxt1, can generate a muscular dystrophy phenotype in Drosophila suggest that investigation of the RNA export pathway in context of the disease is warranted.…”

“…Interestingly both MBNL1 and muscleblind ( mbl ), the Drosophila orthologue of MBNL1, produce abundant circular RNAs [11]. Moreover, Mbl protein is implicated in regulation of production of its own circRNA [11], although the MBNL1 circRNA has not yet been implicated in myotonic dystrophy [19].…”

Metformin Reduces the Senescence of Renal Tubular Epithelial Cells in Diabetic Nephropathy via the MBNL1/miR-130a-3p/STAT3 Pathway

“…In addition, MBNL1 is an RBP consisting of 343 amino acids and located at chromosome 3q25.1-q25.2, and its location imbalance in cells is an important pathogenic factor for myotonic dystrophy [16]. MBNL1 can bind to several RNAs to regulate their functions including stability [17]. It can bind to two tumor suppressors drebrin-like protein (DBNL) and transforming acidic coiled-coil containing protein 1 (TACC1) to maintain their stability and thus inhibit the invasion and metastasis of breast cancer [18].…”

Novel autoregulatory cases of alternative splicing coupled with nonsense-mediated mRNA decay

“…The phosphorylated UPF1 recruits the endonuclease SMG6 and other 31 factors causing deadenylation and decapping, targeting the cleaved mRNA for degradation by cellular 32 exonucleases [5]. Other models propose that sensing the distinction between a normal termination codon 33 and a PTC depends on the distance between the terminating ribosome and the poly(A) tail, in which the 34 interaction of eRF3 with PABPC1 is important, or that an early ribosome release caused by the PTC 35 exposes the downstream unprotected mRNA to degradation by nucleases independently of EJCs [6]. 36 It has been increasingly reported over past years that NMD is not only dedicated to the destruction of 37 PTC-containing mRNAs that appear as a result of nonsense mutations or splicing errors, but that it also 38 plays a key role in regulating the expression of a broad class of physiological transcripts [7,8].…”

“…Studies have shown that mutations 61 in RBP binding sites abolish this negative feedback, while RBP overexpression leads to the increased 62 fraction of unproductively-spliced mRNA [25]. To date, many genes that utilize this mechanism are 63 known, including SR proteins [14,26,27], hnRNP family members [28][29][30], TDP-43 [31,32], TRA2β [33], 64 MBNL [34,35], PTB [36], CHTOP [37], FUS [38], and core spliceosomal and ribosomal proteins [39- 65 41]. Besides autoregulation, some RBPs use AS-NMD to cross-regulate the expression of their family 66 members.…”