Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing

Area of Science:

• Molecular Biology
• RNA Metabolism
• Muscle Biology

Background:

• Polyadenylate binding protein 1 (PABPN1) is crucial for RNA metabolism but its role in skeletal muscle is understudied.
• Mutations in PABPN1 cause oculopharyngeal muscular dystrophy (OPMD), a muscle-wasting disease.
• Matrin 3 (MATR3) mutations are linked to distal myopathy and amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To identify novel PABPN1 interacting proteins in mouse skeletal muscle.
• To investigate the functional relationship between PABPN1 and its interactors in myogenesis and RNA processing.
• To explore the role of PABPN1 and its interactors in the context of OPMD.

Main Methods:

• Co-immunoprecipitation and mass spectrometry to identify PABPN1 interactors.
• Myogenesis assays to assess the role of PABPN1 and MATR3.
• Analysis of RNA processing events including alternative polyadenylation and intron retention.
• Investigation of long non-coding RNA (lncRNA) Neat1 regulation and paraspeckle function.
• Assessment of paraspeckle morphology in a mouse model of OPMD.

Main Results:

• Matrin 3 (MATR3) was identified as a novel interactor of PABPN1 in mouse skeletal muscle.
• Both PABPN1 and MATR3 are essential for myogenesis.
• MATR3 regulates alternative polyadenylation, intron retention, and binds/regulates lncRNA Neat1.
• PABPN1 and MATR3 are required for paraspeckle formation and adenosine to inosine (A to I) RNA editing of Ctn RNA.
• Altered paraspeckle morphology was observed in a mouse model of OPMD with alanine-expanded PABPN1.

Conclusions:

• PABPN1 and MATR3 form a functional complex in skeletal muscle, regulating RNA processing and paraspeckle function.
• This interaction provides a mechanistic link between PABPN1 and MATR3 in muscle biology.
• The findings offer insights into the pathogenesis of OPMD and potentially other neuromuscular disorders involving PABPN1 and MATR3.