Chen, X. X. L. | Search bioRxiv

bioRxiv2023

Differential effects of MATR3 variants on its cryptic splicing repression function

MATR3 is an RNA-binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease-associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS-linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease-associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease-associated variants impact MATR3 cryptic splicing repression function.

molecular biology↗

bioRxiv2019

Egg activation triggers clearance of maternally deposited RNA binding proteins

The maternal-to-zygotic transition (MZT) is a conserved step in animal development, where control is passed from the maternal genome to the zygotic one. Although the MZT is typically considered from its impact on the transcriptome, we previously found that three maternally deposited Drosophila RNA binding proteins (ME31B, Trailer Hitch [TRAL], and Cup) are also cleared during the MZT by unknown mechanisms. Here, we show that these proteins are degraded by the ubiquitin-proteasome system. Kondo, an E2 conjugating enzyme, and the E3 CTLH ligase are required for the destruction of ME31B, TRAL, and Cup. Importantly, despite occurring hours earlier, egg activation establishes the timer for clearance of these proteins by activating the Pan Gu kinase, which in turn stimulates translation of Kondo mRNA. In other words, egg activation triggers a series of regulatory events that culminate in the degradation of maternally deposited RNA binding proteins several hours later. Clearance of the maternal protein dowry thus appears to be a coordinated, but as-yet underappreciated, aspect of the MZT.\n\nHIGHLIGHTSO_LIDegradation of ME31B requires the PNG kinase, but not fertilization\nC_LIO_LIThe ubiquitin-proteasome system degrades ME31B via CTLH E3 ligase and the UBC-E2H/Kondo ubiquitin-conjugating enzyme\nC_LIO_LIThe association of ME31B with the CTLH complex does not require PNG activity\nC_LIO_LIPNG kinase mediates the translational upregulation of Kondo at egg activation\nC_LI

developmental biology↗