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Small Proline-Rich Protein 2B Drives Stress-Dependent P53 Degradation and Fibroblast Proliferation in Heart Failure

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Small Proline-Rich Protein 2B Drives Stress-Dependent P53 Degradation and Fibroblast Proliferation in Heart Failure Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure Ryan M. Burkea, Janet K. Lighthousea, Pearl Quijadaa, Ronald A. Dirkx Jr.a, Alexander Rosenbergb,c, Christine S. Moravecd, Jeffrey D. Alexise, and Eric M. Smalla,e,f,g,1 aAab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642; bDivision of Allergy, Immunology, and Rheumatology Research, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642; cDepartment of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; dDepartment of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195; eDepartment of Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642; fDepartment of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642; and gDepartment of Biomedical Engineering, University of Rochester, Rochester, NY 14642 Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 1, 2018 (received for review October 5, 2017) Heart disease is associated with the accumulation of resident leading to self-destruction. The mechanisms controlling the bal- cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), ance between MDM2-autoubiquitination and MDM2-dependent leading to the development of pathological fibrosis and heart p53 degradation are complex, context dependent, and incompletely failure. However, the mechanisms underlying resident CF pro- understood (9). liferation remain poorly defined. Here, we report that small proline- We conducted an RNA sequencing (RNA-seq) screen to identify rich protein 2b (Sprr2b) is among the most up-regulated genes in genes that are differentially expressed in mouse CFs during physi- CFs during heart disease. We demonstrate that SPRR2B is a regula- ological (swim training) or pathological [transverse aortic constric- tory subunit of the USP7/MDM2-containing ubiquitination complex. tion (TAC)] remodeling. Small proline-rich protein 2b (Sprr2b)was SPRR2B stimulates the accumulation of MDM2 and the degradation among the genes that were most profoundly up-regulated in path- of p53, thus facilitating the proliferation of pathological CFs. Fur- ological remodeling and lost in physiological remodeling. Here, we thermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases describe an interaction between Sprr2b and a nuclear complex of in response to TGF-β1 signaling and free-radical production poten- USP7, MDM2, and p53. Sprr2b promotes MDM2 accumulation tiates SPRR2B activity and cell cycle progression. Knockdown of the and p53 degradation, and accelerates cell cycle progression spe- Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates cifically in CFs. We demonstrate that TGF-β1 and reactive oxygen USP7/MDM2 binding and p53 degradation, leading to CF cell cycle species (ROS) signaling potentiates both Sprr2b gene expression SPRR2B arrest. Importantly, expression is elevated in cardiac tissue and nonreceptor tyrosine kinase (NRTK)-dependent phosphory- from human heart failure patients and correlates with the prolifer- lation of the Sprr2b protein, facilitating USP7/MDM2 interaction ative state of patient-derived CFs in a process that is reversed by and the degradation of p53. Importantly, we show that SPRR2B is insulin growth factor-1 signaling. These data establish SPRR2B as a significantly enriched within the cardiac interstitium in human HF. unique component of the USP7/MDM2 ubiquitination complex that Indeed, SPRR2B expression positively correlates with proliferation drives p53 degradation, CF accumulation, and the development of of CFs isolated from human HF patients. Taken together, our study pathological cardiac fibrosis. fibroblast | heart | p53 | proliferation | SPRR2B Significance Heart disease is associated with the development of fibrosis, a eart disease is accompanied by hypertrophic growth and type of scarring that impedes cardiac function. The primary cel- pathological remodeling of the myocardium and is the leading H lular source of cardiac fibrosis is the resident cardiac fibroblast. We cause of death in the United States (1, 2). Activated cardiac fi- found that cardiac fibroblasts from human heart failure patients broblasts (CFs), often called myofibroblasts, accumulate in heart or a mouse model of heart disease express excessive amounts of disease and secrete extracellular matrix (ECM), driving the devel- the SPRR2B protein. We provide evidence that SPRR2B is a signal- opment of cardiac fibrosis (3, 4). Cardiac fibrosis is a form of responsive regulatory subunit of the p53 ubiquitination complex scarring that replaces necrotic tissue and provides structural support that stimulates the destruction of p53 and the accumulation of to the expanding myocardium, but does so at the expense of cardiac pathological fibroblasts. This study defines a unique mechanism function and ultimately leads to heart failure (HF) (1). In contrast, of cell cycle control that is dysfunctional in heart disease and may physiological hypertrophic growth in response to exercise improves drive the development pathological fibrosis. cardiac function and attenuates the development of fibrosis. The mechanisms that control fibroblast accumulation and activation Author contributions: R.M.B. and E.M.S. designed research; R.M.B., J.K.L., P.Q., and R.A.D. specifically in pathological remodeling are poorly defined. performed research; C.S.M. and J.D.A. contributed new reagents/analytic tools; R.M.B., Similarities between pathological fibroblast activation and J.K.L., P.Q., R.A.D., A.R., and E.M.S. analyzed data; and R.M.B. and E.M.S. wrote the paper. unrestrained cell proliferation in cancerous tumors are evident Conflict of interest statement: E.M.S. is the recipient of a research grant from Novartis Pharmaceuticals. (5); the p53 tumor suppressor has recently been linked to lung This article is a PNAS Direct Submission. and cardiac fibrosis, and is also thought to impact CF plasticity Published under the PNAS license. during pressure overload and ischemic injury (6, 7). p53 activates Data deposition: The data reported in this paper have been deposited in the Gene Ex- cell cycle exit genes such as cyclin-dependent kinase inhibitor 1a pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. (Cdkn1a) as well as proapoptotic genes such as BAX (8). p53 is a GSE89885). substrate for the E3 ubiquitin ligase MDM2, which targets 1To whom correspondence should be addressed. Email: [email protected]. p53 for proteasome-mediated degradation, relieving constraints This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. on cell cycle. USP7 is an MDM2 deubiquitinase that stabilizes 1073/pnas.1717423115/-/DCSupplemental. MDM2, whereas MDM2 might otherwise ubiquitinate itself, Published online March 26, 2018. E3436–E3445 | PNAS | vol. 115 | no. 15 www.pnas.org/cgi/doi/10.1073/pnas.1717423115 Downloaded by guest on September 26, 2021 describes a unique stress-dependent mechanism regulating strated robust expression of SPRR2B following TAC, localizing to PNAS PLUS MDM2-dependent p53 degradation that controls pathological both the cytoplasm and nucleus of cardiac interstitial cells, but CF accumulation. not CMs (Fig. 1E). In contrast, SPRR2B-expressing cells were rarely found in the heart of control animals and were undetect- Results able in swim-trained animals. Sprr2b Expression Is Induced in CFs During Pathologic Remodeling. To identify genes that might underlie the divergent fibrotic re- TGF-β1 and H2O2 Synergistically Induce Sprr2b Expression, Which Is sponse of the heart to pathological and physiological hypertro- Required for CF Proliferation. Since HF is associated with TGF-β phic growth, we performed RNA-seq on CFs isolated from mice signaling and increased ROS burden, we evaluated the potential subjected to 10 days of left ventricle pressure overload or swim contribution of SPRR2B to TGF-β and ROS-induced changes in training (Fig. S1A and B) (10–14). This study identified 2,454 fibroblast plasticity. Treatment of CFs with TGF-β1 (10 ng/mL) genes that changed in endurance exercise and 4,051 genes that and H2O2 (50 μM) was found to maximize fibroblast activation changed in response to TAC (Fig. 1A). One of the most affected and proliferation while minimizing cell death (Fig. S2). TGF-β1and genes was Sprr2b (Fig. 1 A and B), which was 4.3-fold up- H2O2 synergistically stimulated the expression of Sprr2b (Fig. 2A) regulated in TAC relative to controls [fragments per kilobase and also led to a synergistic increase in CF proliferation (Fig. 2B). per million reads (FPKM) 8.099 versus 1.890] and 9.1-fold down- In contrast, myofibroblast genes were not synergistically induced regulated in swim relative to controls (FPKM 0.207 versus 1.890). by TGF-β1andH2O2 (Fig. 2C). To determine whether SPRR2B We also identified five others members of the Sprr2 family (Sprr2a, impacts fibroblast activation and/or proliferation, we transfected -d, -e, -h, -i) that were only moderately up-regulated in TAC vehicle or TGF-β1/H2O2–treated CFs with a plasmid driving the compared with swim (Fig. 1B and Fig. S1C). qRT-PCR confirmed expression of human SPRR2B. SPRR2B did not have an effect on the changes in Sprr2b expression during physiological and patho- Acta2 or Col1a1 expression (Fig. 2D), but significantly
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