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Auto-Fatty Acylation of Transcription Factor RFX3 Regulates Ciliogenesis

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Auto-Fatty Acylation of Transcription Factor RFX3 Regulates Ciliogenesis Auto-fatty acylation of transcription factor RFX3 regulates ciliogenesis Baoen Chena, Jixiao Niua, Johannes Kreuzerb,c, Baohui Zhenga, Gopala K. Jarugumillia, Wilhelm Haasb,c, and Xu Wua,1 aCutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129; bMassachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; and cDepartment of Medicine, Harvard Medical School, Charlestown, MA 02129 Edited by Marilyn D. Resh, Memorial Sloan-Kettering Cancer Center, New York, NY, and accepted by Editorial Board Member Kathryn V. Anderson July 31, 2018 (received for review January 17, 2018) Defects in cilia have been associated with an expanding human mature β-cell function, and glucokinase gene expression (22, 27). disease spectrum known as ciliopathies. Regulatory Factor X 3 Interestingly, RFX3- and RFX6-knockout mice share many (RFX3) is one of the major transcription factors required for cilio- common defects in islet cell differentiation and mature β-cell genesis and cilia functions. In addition, RFX3 regulates pancreatic function, suggesting that RFX3 and RFX6 may coordinately islet cell differentiation and mature β-cell functions. However, how regulate a set of genes associated with pancreas development RFX3 protein is regulated at the posttranslational level remains and β-cell function (22, 28). A recent study observed a re- poorly understood. Using chemical reporters of protein fatty ac- markably strong correlation between RFX transcription factors ylation and mass spectrometry analysis, here we show that and type 2 diabetes (T2D) risk, suggesting that RFX factors may RFX3 transcriptional activity is regulated by S-fatty acylation at a play a significant role in the genetic component of T2D pre- highly conserved cysteine residue in the dimerization domain. Sur- disposition (29). Furthermore, a recent genome-wide association prisingly, RFX3 undergoes enzyme-independent, “self-catalyzed” study (GWAS) revealed that RFX3 is highly associated with gout auto-fatty acylation and displays preferences for 18-carbon stearic arthritis, which is one of the most common types of inflammatory acid and oleic acid. The fatty acylation-deficient mutant of arthritis, suggesting that RFX3 might also play a role in the auto- RFX3 shows decreased homodimerization; fails to promote ciliary immune regulation (30). RFX1/3 double-knockout mice devel- gene expression, ciliogenesis, and elongation; and impairs Hedge- oped rapidly progressive hearing loss, indicating that RFX3 and hog signaling. Our findings reveal a regulation of RFX3 transcription RFX1 may coordinately regulate genes involved in mice hearing factor and link fatty acid metabolism and protein lipidation to the (31). This is supported by the ChIP-sequencing (ChIP-seq) anal- regulation of ciliogenesis. ysis, which showed significant overlap of target genes between RFX1 and RFX3 (27, 31). RFX3 | fatty acylation | ciliogenesis | autoacylation | palmitoylation RFX family proteins have a conserved winged-helix DNA- binding domain in the N terminus, and most members contain a ilia are conserved organelles present on the surface of most conserved dimerization domain in the C terminus (10, 13, 32, Cvertebrate cells, sensing diverse extracellular signals crucial for 33). Although RFX family proteins can bind to DNA as a cell proliferation, differentiation, polarity, and tissue homeostasis monomer in vitro, numerous studies have suggested that RFX (1–4). For example, cilia are critical for Hedgehog (Hh) pathway, dimerization or interactions with partner proteins is critical for – and many pathway components are required to localize to cilia for its transcriptional activity (10, 33 42). Various lines of evidence – signal transduction. Therefore, loss of cilia leads to impairment of have shown that RFX1 4 and RFX6 can form homodimers Hh signaling activities (2). An increasing number of human de- and diverse heterodimers (14, 37, 40, 43), supporting the notion velopmental and degenerative disorders have been attributed to that dimerization is essential for RFX transcription factors to defects in cilia formation and functions, which are collectively termed ciliopathies (5–8). Many ciliopathies are caused by dis- Significance ruption of ciliogenesis that is transcriptionally regulated by Regu- latory Factor X (RFX) transcription factors (8–11). RFX was Regulatory Factor X 3 (RFX3) is one of the key transcription identified initially as a regulatory protein that binds to the X-box of factors involved in cilia formation and functions. Our study re- a major histocompatibility complex (MHC) class II promoter (12). veals that auto-fatty acylation is a critical regulatory mechanism RFX family transcription factors are conserved across a wide range for RFX3 transcriptional activities. Fatty acylation of RFX3 is of species, including Saccharomyces cerevisiae, Schizosaccharomyces required for its dimerization, leading to transcription of cilia- prombe, Caenorhabditis elegans, Drosophila melanogaster,andver- associated genes. More importantly, fatty acylation of RFX3 tebrates (13). Eight members of human RFX transcription factors regulates ciliogenesis and Hedgehog signaling pathways, which (RFX1–8) have been identified (14). RFX factors have conserved are associated with developmental and degenerative disorders and critical roles in controlling ciliary gene expression and cilia known as ciliopathies. Our results indicate a major role of auto- formation, including RFX1–4 in vertebrates, DAF19 in C. elegans, fatty acylation in the regulation of RFX3 function and cilio- and RFX in D. melanogaster (9, 10, 15–21). RFX1, RFX2, and genesis, providing a potential link between deregulation of fatty RFX3 are the closest homologs of DAF19 in C. elegans and RFX acid metabolism to ciliopathies and diabetes. in D. melanogaster (13). In particular, RFX3 plays a critical role in Author contributions: B.C., W.H., and X.W. designed research; B.C., J.N., J.K., B.Z., and ciliogenesis. It has been shown that RFX3 is broadly expressed G.K.J. performed research; J.N., B.Z., and G.K.J. contributed new reagents/analytic tools; in ciliated cells and is essential for growth and function of cilia in B.C., J.K., W.H., and X.W. analyzed data; and B.C. and X.W. wrote the paper. ciliated cells, including embryonic node cells, brain ependymal The authors declare no conflict of interest. cells, pancreatic islet cells, neuronal cells, and basal cells (10, 11, This article is a PNAS Direct Submission. M.D.R. is a guest editor invited by the 17, 18, 22–24). RFX3-deficient mice exhibit defective cilia in the Editorial Board. brain and pancreas, with hallmarks of ciliopathies including left– Published under the PNAS license. right asymmetry defects, hydrocephalus, corpus callosum agenesis, 1To whom correspondence should be addressed. Email: [email protected]. and abnormal thalamocortical tract formation (17, 22, 23, 25, 26). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. In addition to regulating ciliogenesis, RFX3 plays an impor- 1073/pnas.1800949115/-/DCSupplemental. BIOCHEMISTRY tant role in regulating pancreatic endocrine cell differentiation, Published online August 20, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1800949115 PNAS | vol. 115 | no. 36 | E8403–E8412 Downloaded by guest on September 27, 2021 cooperatively regulate target genes. However, how different RFX C. elegans (DAF-19) and found one evolutionarily conserved factors cooperate with each other in regulating target gene ex- cysteine residue (Cys544) at the dimerization domain of RFX3 pression remains elusive. In addition, how RFX factors are regu- (Fig. 1D). Cys544 is also conserved in RFX1, RFX2, and RFX3 lated by posttranslational modifications is largely unknown. (SI Appendix, Fig. S3). According to the CSS-Palm software Protein fatty acylation is an important cotranslational or (csspalm.biocuckoo.org/online.php) for the prediction of protein posttranslational modification of proteins, in which various fatty palmitoylation sites, cysteine residues including Cys429, Cys431, acids are covalently attached to proteins. Fatty acylation plays Cys542, Cys544, and Cys739 are potential palmitoylation sites important roles in protein trafficking and localization, stability, with relatively high scores. To confirm the fatty acylated cysteine and binding to cofactors (44). Bioorthogonal chemical reporters residues, we constructed a series of RFX3 mutants, in which the have been widely used to detect potential fatty acylated proteins cysteine residues of RFX3 were mutated to serines. HEK293A in previous studies (45, 46). Here we show that RFX1 and cells were transfected with Flag-tagged wild-type (WT) RFX3 RFX3 are S-fatty acylated proteins using chemical reporter and or the mutant constructs (C429S, C431S, C542S, C544S, and mass spectrometry (MS) analysis. RFX3 is fatty acylated through C739S) and metabolically labeled with Alk-C16. Streptavidin an enzyme-independent and self-catalyzed autoacylation process blot revealed that only the mutation of Cys544 could completely and displays preferences toward 18-carbon fatty acids, such as abolish RFX3 fatty acylation, whereas the mutation of other stearic acid and oleic acid. Furthermore, we identified that cysteine residues had little effect (Fig. 1E). Notably, Cys542 is RFX3 is fatty acylated at an evolutionarily conserved cysteine very close to Cys544 and relatively conserved across different residue in the dimerization
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