ITSN1 regulates SAM68 solubility through SH3 domain interactions with SAM68 proline-rich motifs
Résumé
SAM68 is an mRNA-binding protein involved in mRNA processing in the nucleus that forms membraneless compartments
called SAM68 Nuclear Bodies (SNBs). We found that intersectin 1 (ITSN1), a multidomain scaffold protein harboring
five soluble SH3 domains, interacts with SAM68 proline-rich motifs (PRMs) surrounded by self-adhesive low complexity
domains. While SAM68 is poorly soluble in vitro, the interaction of ITSN1 SH3 domains and mRNA with SAM68 enhances
its solubility. In HeLa cells, the interaction between the first ITSN1 SH3 domain (SH3A) and P0, the N-terminal PRM of
SAM68, induces the dissociation of SNBs. In addition, we reveal the ability of another SH3 domain (SH3D) of ITSN1 to
bind to mRNAs. ITSN1 and mRNA may thus act in concert to promote SAM68 solubilization, consistent with the absence
of mRNA in SNBs in cells. Together, these results support the notion of a specific chaperoning of PRM-rich SAM68 within
nuclear ribonucleoprotein complexes by ITSN1 that may regulate the processing of a fraction of nuclear mRNAs, notably
SAM68-controlled splicing events related to higher neuronal functions or cancer progression. This observation may also
serve as a putative model of the interaction between other PRM-rich RBPs and signaling proteins harboring SH3 domains.
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