GSK3- and PRMT-1-dependent modifications of desmoplakin control desmoplakin-cytoskeleton dynamics.
Intermediate filament (IF) attachment to intercellular junctions is required for skin and heart integrity, but how the strength and dynamics of this attachment are modulated during normal and pathological remodeling is poorly understood. We show that glycogen synthase kinase 3 (GSK3) and protein arginine methyltransferase 1 (PRMT-1) cooperate to orchestrate a series of posttranslational modifications on the IF-anchoring protein desmoplakin (DP) that play an essential role in coordinating cytoskeletal dynamics and cellular adhesion. Front-end electron transfer dissociation mass spectrometry analyses of DP revealed six novel serine phosphorylation sites dependent on GSK3 signaling and four novel arginine methylation sites including R2834, the mutation of which has been associated with arrhythmogenic cardiomyopathy (AC). Inhibition of GSK3 or PRMT-1 or overexpression of the AC-associated mutant R2834H enhanced DP-IF associations and delayed junction assembly. R2834H blocked the GSK3 phosphorylation cascade and reduced DP-GSK3 interactions in cultured keratinocytes and in the hearts of transgenic R2834H DP mice. Interference with this regulatory machinery may contribute to skin and heart diseases.
Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
Lauren V
LV
Albrecht
Department of Chemistry and Department of Pathology, University of Virginia, Charlottesville, VA 22904.
Lichao
L
Zhang
Department of Chemistry and Department of Pathology, University of Virginia, Charlottesville, VA 22904.
Jeffrey
J
Shabanowitz
Department of Pediatrics (Cardiology), Baylor College of Medicine, Texas Children's Hospital, Houston, TX 45229.
Enkhsaikhan
E
Purevjav
Department of Pediatrics (Cardiology), Baylor College of Medicine, Texas Children's Hospital, Houston, TX 45229.
Jeffrey A
JA
Towbin
Department of Chemistry and Department of Pathology, University of Virginia, Charlottesville, VA 22904 Department of Chemistry and Department of Pathology, University of Virginia, Charlottesville, VA 22904.
Donald F
DF
Hunt
Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 kgreen@northwestern.edu.
Kathleen J
KJ
Green
D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012871:Skin Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C495294:DSP protein, human; D051180:Desmoplakins; C495295:Dsp protein, mouse; D012097:Repressor Proteins; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D038362:Glycogen Synthase Kinase 3