UMass Chan Medical School Faculty Publications

Title

PAD2-mediated citrullination of Fibulin-5 promotes elastogenesis

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

2021-08-01

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Chemical and Pharmacologic Phenomena | Enzymes and Coenzymes

Abstract

The 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.

Keywords

Citrullination, Deiminase, Deimination, Elastic fiber, Emphysema, Fibulin-5, Lung compliance

DOI of Published Version

10.1016/j.matbio.2021.07.001

Source

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

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Matrix biology : journal of the International Society for Matrix Biology

PubMed ID

34274450

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