Salinger, Ari J.
Rosas, Ivan O.
Reinhardt, Dieter P.
Thompson, Paul R.
UMass Chan AffiliationsThompson Lab
Department of Biochemistry and Molecular Pharmacology
Amino Acids, Peptides, and Proteins
Biochemical Phenomena, Metabolism, and Nutrition
Biochemistry, Biophysics, and Structural Biology
Chemical and Pharmacologic Phenomena
Enzymes and Coenzymes
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AbstractThe formation of elastic fibers is active only in the perinatal period. How elastogenesis is developmentally regulated is not fully understood. Citrullination is a unique form of post-translational modification catalyzed by peptidylarginine deiminases (PADs), including PAD1-4. Its physiological role is largely unknown. By using an unbiased proteomic approach of lung tissues, we discovered that FBLN5 and LTBP4, two key elastogenic proteins, were temporally modified in mouse and human lungs. We further demonstrated that PAD2 citrullinated FBLN5 preferentially in young lungs compared to adult lungs. Genetic ablation of PAD2 resulted in attenuated elastogenesis in vitro and age-dependent emphysema in vivo. Mechanistically, citrullination protected FBLN5 from proteolysis and subsequent inactivation of its elastogenic activity. Furthermore, citrullinated but not native FBLN5 partially rescued in vitro elastogenesis in the absence of PAD activity. Our data uncover a novel function of citrullination, namely promoting elastogenesis, and provide additional insights to how elastogenesis is regulated.
Sun B, Tomita B, Salinger A, Tilvawala RR, Li L, Hakami H, Liu T, Tsoyi K, Rosas IO, Reinhardt DP, Thompson PR, Ho IC. PAD2-mediated citrullination of Fibulin-5 promotes elastogenesis. Matrix Biol. 2021 Aug;102:70-84. doi: 10.1016/j.matbio.2021.07.001. Epub 2021 Jul 15. PMID: 34274450; PMCID: PMC8502204. Link to article on publisher's site