Links between mRNA splicing, mRNA quality control, and intellectual disability

Abstract

In recent years, the impairment of RNA binding proteins that play key roles in the post-transcriptional regulation of gene expression has been linked to numerous neurological diseases. These RNA binding proteins perform critical mRNA processing steps in the nucleus, including splicing, polyadenylation, and export. In many cases, these RNA binding proteins are ubiquitously expressed raising key questions about why only brain function is impaired. Recently, mutations in the ZC3H14 gene, encoding an evolutionarily conserved, polyadenosine RNA binding protein, have been linked to a nonsyndromic form of autosomal recessive intellectual disability. Thus far, research on ZC3H14 and its Nab2 orthologs in budding yeast and Drosophila reveals that ZC3H14/Nab2 is important for mRNA processing and neuronal patterning. Two recent studies now provide evidence that ZC3H14/Nab2 may function in the quality control of mRNA splicing and export and could help to explain the molecular defects that cause neuronal dysfunction and lead to an inherited form of intellectual disability. These studies on ZC3H14/Nab2 reveal new clues to the puzzle of why loss of the ubiquitously expressed ZC3H14 protein specifically affects neurons.

Figure 1. Domain structure of S. cerevisiae Nab2, Drosophila melanogaster dNab2, human ZC3H14 Isoform 1-4 polyadenosine RNA binding protein

The ZC3H14/Nab2 proteins contain the following domains: an N-terminal Pro-Trp-Ile (PWI)-like fold domain (red), important for protein-protein interaction and mRNA export in Nab2 ^{[13, 14, 18, 19, 31]}, a Glu (Q)-rich domain (green), an RGG motif/predicted classical nuclear localization signal (cNLS) (orange), important for localization to the nucleus in Nab2 [13], and a C-terminal tandem Cys3^His (CCCH) zinc finger domain (blue), critical for specific binding to polyadenosine RNA ^{[10, 11, 20]}. The Arg154Stop (R154X) premature termination codon mutation in ZC3H14 linked to intellectual disability that eliminates ZC3H14 Isoform 1-3 ^[6] is depicted above ZC3H14 Isoform 1. Amino acid positions of domains are shown below each protein.

Figure 2. Model for ZC3H14/Nab2 function in quality control of mRNA splicing and export

ZC3H14/Nab2 binds to the poly(A) tail of a transcript and checks for interaction with early splicing factors, such as branchpoint recognition factors, U2AF2/Mud2 and BBP/Msl5, to detect improperly spliced and unspliced pre-mRNA. If ZC3H14/Nab2 binds to splicing factors on the pre-mRNA, ZC3H14/Nab2 could mark the transcript as unspliced, retain the transcript in the nucleus, and trigger recruitment of the RNA exosome (Exo) to the transcript for degradation. If ZC3H14/Nab2 does not bind to splicing factors, the mRNA transcript could be marked as spliced and ZC3H14/Nab2, together with other export factors, could stabilize and remodel the transcript and target the transcript to the nuclear pore complex via interaction with nuclear pore-associated proteins (Mlp1) for export to the cytoplasm.