A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD

Abstract

	•Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa.
	•Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa.
	•In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa.
	•Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

Keywords

circ-RNA translation / h4k16ac / lipid dyshomeostasis / nuclear transport / transcription

References

[1] PByrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62:S47-S64.

[2] Portincasa P, Krawczyk M, Smyk W, Lammert F, Di Ciaula A. COVID-19 and nonalcoholic fatty liver disease: two intersecting pandemics. Eur J Clin Invest. 2020;50:e13338.

[3] Estes C, Anstee QM, Arias-Loste MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016–2030. J Hepatol. 2018;69:896-904.

[4] Chen Z, Yu Y, Cai J, Li H. Emerging Molecular Targets for Treatment of Nonalcoholic Fatty Liver Disease. Trends Endocrinol Metab. 2019;30:903-914.

[5] Manne V, Handa P, Kowdley KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis. 2018;22:23-37.

[6] Aron-Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Metabolism and metabolic disorders and the microbiome: the intestinal microbiota associated with obesity, lipid metabolism, and metabolic health-pathophysiology and therapeutic strategies. Gastroenterology. 2021;160:573-599.

[7] Saaoud F, Drummer IVC, Shao Y, et al. Circular RNAs are a novel type of non-coding RNAs in ROS regulation, cardiovascular metabolic inflammations and cancers. Pharmacol Ther. 2021;220:107715.

[8] Zeng Y, Zheng Z, Liu F, Yi G. Circular RNAs in metabolism and metabolic disorders. Obes Rev. 2021, 22:e13220.

[9] Zhao Q, Liu J, Deng H, et al. Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell. 2020;183:76-93.

[10] Pamudurti NR, Bartok O, Jens M, et al. Translation of CircRNAs. Mol Cell. 2017;66:9-21.

[11] Li H, Lan T, Liu H. IL-6-induced cGGNBP2 encodes a protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma. Hepatology. 2022;75:1402-1419.

[12] Du WW, Xu J, Yang W, et al. A neuroligin isoform translated by circNlgn contributes to cardiac remodeling. Circ Res. 2021;129:568-582.

[13] Yuan X, Diao J, Du A, Wen S, Zhou L, Pan Y. Circular RNA expression profiles and features in NAFLD mice: a study using RNA-seq data. J Transl Med. 2020;18:476.

[14] Shi Y, Jia X, Xu J. The new function of circRNA: translation. Clin Transl Oncol. 2020;22:2162-2169.

[15] Pan Z, Zheng J, Zhang J, et al. A novel protein encoded by exosomal CircATG4B induces oxaliplatin resistance in colorectal cancer by promoting autophagy. Adv Sci (Weinh). 2022;9(35):e2204513.

[16] Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N6-methyladenosine. Cell Res. 2017;27:626-641.

[17] Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117-120.

[18] Wakabayashi S, Pang T, Su X, Shigekawa M. A novel topology model of the human Na(+)/H(+) exchanger isoform 1. J Biol Chem. 2000;275:7942-7949.

[19] Poon IK, Jans DA. Regulation of nuclear transport: central role in development and transformation. Traffic. 2005;6:173-186.

[20] Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003;423:550-555.

[21] Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol. 2009;11:397-408.

[22] Liang J, Zubovitz J, Petrocelli T, et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153-1160.

[23] Lu J, Wu T, Zhang B, et al. Types of nuclear localization signals and mechanisms of protein import into the nucleus. Cell Commun Signal. 2021;19:60.

[24] Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261-1274.

[25] Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28:516-524.

[26] Tabuchi A, Ihara D. Regulation of dendritic synaptic morphology and transcription by the SRF cofactor MKL/MRTF. Front Mol Neurosci. 2021;14:767842.

[27] Kim H, Kim K, Choi J, et al. p53 requires an intact C-terminal domain for DNA binding and transactivation. J Mol Biol. 2012;415:843-854.

[28] Millán-Zambrano G, Burton A, Bannister AJ, Schneider R. Histone post-translational modifications—cause and consequence of genome function. Nat Rev Genet. 2022;23:563-580.

[29] Samata M, Alexiadis A, Richard G, et al. Intergenerationally maintained histone H4 lysine 16 acetylation is instructive for future gene activation. Cell. 2020;182:127-144.

[30] Pessoa Rodrigues C, Chatterjee A, Wiese M, Stehle T, et al. Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice. Nat Commun. 2021;12:6212.

[31] Rada P, González-Rodríguez Á, García-Monzón C, Valverde ÁM. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver. Cell Death Dis. 2020;11:802.

[32] Qi Z, Hu L, Zhang J, et al. PCSK9 (proprotein convertase subtilisin/Kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation. 2021;143:45-61.

[33] Xu X, Poulsen KL, Wu L, et al. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther. 2022;7:287.

[34] Al Saedi A, Debruin DA, Hayes A, Hamrick M. Lipid metabolism in sarcopenia. Bone. 2022;164:116539.

[35] Tarantino G, Sinatti G, Citro V, Santini SJ, Balsano C. Sarcopenia, a condition shared by various diseases: can we alleviate or delay the progression. Intern Emerg Med. 2023;18(7):1887-1895.

[36] Zhou J, Wan J, Gao X, Zhang X, Jaffrey SR, Qian SB. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 2015;526:591-594.

[37] Fang L, Teng H, Wang Y, et al. SET1A-mediated mono-methylation at K342 regulates YAP activation by blocking its nuclear export and promotes tumorigenesis. Cancer Cell. 2018;34:103-118.

[38] Hao N, Budnik BA, Gunawardena J, O’Shea EK. Tunable signal processing through modular control of transcription factor translocation. Science. 2013;339:460-464.

[39] Kuchay MS, Martínez-Montoro JI, Kaur P, Fernández-García JC, Ramos-Molina B. Non-alcoholic fatty liver disease-related fibrosis and sarcopenia: an altered liver-muscle crosstalk leading to increased mortality risk. Ageing Res Rev. 2022;80:101696.

[40] Zhao L, Zhang C, Luo X, et al. CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis. J Hepatol. 2018;69:705-717.

[41] Nan P, Dong X, Bai X, et al. Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin αvβ3/CD36-mediated activation of the MAPK pathway. Cancer Lett. 2022;528:59-75.

[42] Mok HL, Cheng KW, Xu Y, et al. Modified Zhenwu decoction suppresses chronic colitis via targeting macrophage CCR2/Fyn/p38 MAPK signaling axis. Phytomedicine. 2024;129:155694.

[43] Sumara G, Formentini I, Collins S, et al. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009;136(2):235-248.

[44] Chen P, Wang R, Liu F, et al. Schizandrin C regulates lipid metabolism and inflammation in liver fibrosis by NF-κB and p38/ERK MAPK signaling pathways. Front Pharmacol. 2023;14:1092151.

[45] Trojanowski J, Frank L, Rademacher A, Mücke N, Grigaitis P, Rippe K. Transcription activation is enhanced by multivalent interactions independent of phase separation. Mol Cell. 2022;82:1878-1893.

[46] Baughman HER, Narang D, Chen W, et al. An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA. J Biol Chem. 2022;298:102349.

[47] Singh S, Sevalkar RR, Sarkar D, Karthikeyan S. Characteristics of the essential pathogenicity factor Rv1828, a MerR family transcription regulator from Mycobacterium tuberculosis. FEBS J. 2018;285:4424-4444.

[48] Zhao F. Dysregulated epigenetic modifications in the pathogenesis of NAFLD-HCC. Adv Exp Med Biol. 2018;1061:79-93.

[49] Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science. 2006;311:844-847.

[50] Zhu X, Chen Z, Shen W, et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct Target Ther. 2021;6(1):245.

RIGHTS & PERMISSIONS

2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.