Associate Professor (Principle Investigator) |School of Life Sciences, Department of Biology

Dr. Rao is currently associate professor and principle investigator at the School of Life Sceinces, SUSTech. He obtained his B.Sc. (2001-2005) and Ph.D. (2007-2011) from National University of Singapore and Nanyang Technological University, respectively. His postdoctoral training was conducted at Johns Hopkins University School of Medicine from 2010-2015. After an assistant investigator appointment at the National Institute of Biological Sciences, he joined SUSTech as an associate professor and principal investigator.

At SUSTech, Dr. Rao’s research group studies the signaling principles of emerging messenger molecules and their metabolic enzymes, with an emphasis on how they are integrated into cellular (patho)physiology via signal transduction pathways under disease micro-environment. They have delineated how IP6 Kinases (IP6K), via converting the signaling metabolite IP6 to IP7, play important roles in cell death, cancer metastasis and DNA damage repair; They've elucidates the upstream signaling pathway leading to IP6K activation, which implicates IP7 as a GPCR messenger. In recent years, the lab has discovered inositol hexakisphosphate (IP6) as an intermolecular “glue” bridging the Cullin Ring E3 Ligases and its inhibitor: the deneddylase COP9 Signalosome,thereby regulating proteastasis which safeguards glucose-induced insulin secretion. These work have been published in high profile journals and attracted attention from the scientific community including journal Commentaries, Highlights, or F1000 recommendations.

Personal Profile

Associate Prof. Rao obtained his B.Sc. (2001-2005) and Ph.D. (2007-2011) from National University of Singapore and Nanyang Technological University, respectively. His postdoctoral training was conducted with Dr. Solomon Snyder at Johns Hopkins University School of Medicine from 2010-2015. After an assistant investigator appointment at the National Institute of Biological Sciences, he joined SUSTech as an associate professor and principal investigator in July 2016.

At SUSTech, Dr. Rao’s research group studies the signaling principles of emerging messenger molecules and their metabolic enzymes, with an emphasis on how they are integrated into cellular (patho)physiology via signal transduction pathways under disease micro-environment. They have delineated how IP6 Kinases (IP6K), via converting the signaling metabolite IP6 to IP7,  play important roles in cell death, cancer metastasis and DNA damage repair; In recent years, the lab has discovered inositol hexakisphosphate (IP6) as an intermolecular “glue” bridging the Cullin Ring E3 Ligases and its inhibitor: the deneddylase COP9 Signalosome,thereby regulating proteastasis. These work have been published in top-tier journals and attracted widespread attention from the scientific community like journal Commentaries, Highlights, or F1000 recommendations.

Representative Publications:

    1. Zhang X#, Li N#, Zhang J#, Zhang Y#, Yang X#, Luo Y, Zhang B, Xu Z, Zhu Z, Yang X, Yan Y, Lin B, Wang S, Chen D, Ye C, Ding Y, Lou M, Wu Q, Hou Z, Zhang K, Liang Z, Wei A, Wang B, Wang C, Jiang N, Zhang W, Xiao G, Ma C, Ren Y, Qi X, Han W, Wang C*Rao F.*. 5-IP7 is a GPCR messenger mediating neural control of synaptotagmin-dependent exocytosis and glucose homeostasis. Nature Metabolism 2021 3, 1400-1414. https://www.nature.com/articles/s42255-021-00468-7
    2. Luo Y, Su Y, Rao F*. Role of NEDD8 and neddylation dynamics in DNA damage response. Genome Instability & Disease 2021 139-149
    3. Lin H#, Yan Y#, Luo Y#, So WY#, Wei X, Zhang X, Yang X, Zhang J, Su Y, Yang X, Zhang B, Zhang KJ, Jiang N, Chow BKC, Han W, Wang F, and Rao F*. IP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion. Nature Communications. 2021 12, 2461. https://doi.org/10.1038/s41467-021-22941-3
    4. Zhang X, Shi S, Su Y, Yang X, He S, Wu J, Zhang J, Rao, F.*. Suramin and NF449 are IP5K inhibitors that disrupt IP6-mediated regulation of cullin RING ligase and sensitize cancer cells to MLN4924/Pevonedistat. J. Biol. Chem. 2020 295,10281-10292.
    5. Lin H. #, Zhang X. #, Liu L.#, Fu QY., Zang CL., Ding Y., Xu ZX., He SN., Yang XL., Wei XY., Mao HB., Cui YS, Wei Yi., Zhou CZ., Du LL., Huang N., Zheng N., Wang T.*, and Rao F.*. Molecular basis of metabolite-dependent Cullin RING ligase deneddylation by the COP9 Siganalosome. Proc. Natl. Acad. Sci. USA. 2020 117, 4117-24.(F1000 recommendation) (Commentary)
    6. Rao F.*, Lin H, Su Y.. Cullin RING ligase regulation by the COP9 Signalosome: Structural Mechanisms and New Physiologic Players. Adv. Exp. Med. Biol. 2020, 1217, 47-60. (Invited Chapter, book “Cullin RING Ligases and Neddylation”).
    7. Zhang X, Rao F.*. Are inositol polyphosphates the missing link in dynamic Cullin RING ligase regulation by the COP9 Signalosome? Biomolecules. "ZOMES" Special Issue: 2019, 9, 349.
    8. 魏文毅*、孙毅*、曹诚、常智杰、陈策实、陈佺、程金科、冯仁田、高大明、胡荣贵、贾立军、姜天霞、金建平、李汇华、李卫、刘翠华、饶枫、商瑜、宋质银、万勇、王平、王占新、吴缅、吴乔、谢旗、谢松波、谢志平、徐平、许执恒、杨波、阳成伟、应美丹、张宏冰、张令强、赵永超、周军、朱军、王琳芳、张宏、王琛、邱小波*. 类泛素蛋白及其中文命名(Ubiquitin-like Proteins and their Chinese Nomenclatures). 科学通报. 2018, 63(25):2564-2569.
    9. Scherer PC.#, Ding Y.#, Liu Z., Xu J., Mao H., Barrow JC., Wei N., Zheng N., Snyder SH*Rao F.*. Inositol hexakisphosphate  (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc. Natl. Acad. Sci. USA2016, 113, 3503-8.
    10. Rao F.#Xu J.#, Fu C.#, Cha JY., Xu R., Gadalla MM., Barrow JC., Snyder SH. Inositol pyrophosphates promote cancer growth and metastasis by antagonizing the tumor suppressor LKB1. Proc. Natl. Acad. Sci. USA2015 112, 1773-8. (Highlighted by Chemistry & Biology)
    11. Rao F.#Xu J.#, Kahn AB., Cha J., Xu R. Tyagi R., Dang Y., Chakraborty A., Snyder SH. Inositol hexakisphosphate kinase-1 mediates assembly/ disassembly of the CRL4-Signalosome complex to regulate DNA repair and cell death. Proc. Natl. Acad. Sci. USA2014, 111, 16005-16010.
    12. Rao F., Cha J., Xu J., Xu R., Vandiver MS., Tokhunt RT., Wu M., Fiedler D., Barrow J., Snyder SH. Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. Mol. Cell. 2014, 54, 119-32.
    13. Tan E.#Rao F.#, Pasunooti S., Pham TH., Soehano I., Turner MS., Liew CW., Lescar J., Pervushin K., Liang Z-X.  Solution structure of the PAS domain of a thermophilic YybT homolog reveals a potential ligand-binding site. J. Biol. Chem. 2013, 288:11949-59.
    14. Rao F., Wang T., Li M., Li Z., Hong N., Zhao H., Yan Y., Lu W., Chen T., Wang W., Lim M., Yuan Y., Liu L., Zeng L., Wei Q., Guan G., Li C., Hong Y. Medaka tertproduces multiple variants with differential expression during differentiation in vitro and in vivo Int. J. Biol. Sci2011, 7(4):426-439.
    15. Rao F., Ji Q., Soehano I., Liang Z-X. Unusual Heme-Binding PAS Domain from YybT Family Proteins. J. Bacteriol. 2011, 193:1543-1551.
    16. Rao F., See RY., Zhang D., Toh DC., Liang Z-X. YybT is a signaling protein that contains a cyclic-di-nucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J. Biol. Chem. 2010, 285:473-82.
    17. Rao F.*, Qi Y., Murugan E., Pasunooti S., Ji Q.. 2’,3’-cAMP hydrolysis by metal-dependent phosphodiesterases containing DHH, EAL, and HD domains is non-specific: implications for PDE screening. Biochem. Biophys. Res. Commun. 2010, 398:500-505.
    18. Rao F., Pasunooti S., Ng Y., Zhuo W., Lim L., Liu AW., Liang Z-X. Enzymatic synthesis of c-di-GMP using a thermophilic diguanylate cyclase. Anal. Biochem. 2009, 389:138-42.
    19. Rao F., Qi Y., Chong HS., Kotaka M., Li B., Lescar J., Tang K., Liang Z-X. The functional role of a conserved loop in EAL domain-based c-di-GMP specific phosphodiesterase. J. Bacteriol. 2009, 191:4722-31. (Commentary: 191:4697-700).
    20. Rao F., Yang Y., Qi Y., Liang Z-X. Catalytic mechanism of C-di-GMP specific phosphodiesterase: a study of the EAL domain containing protein RocR from Psudomonas aeruginosa. J. Bacteriol. 2008, 190:3622-31. (F1000  recommendation)

    (*= Corresponding Author; #=Co-first Author

Research

1. Signaling Principles of the Inositol Pyrophosphate IP7 (Fig 1)

The main interest of our group is to elucidate the function and mechanism of small molecules that are emerging messengers. The GPCR IP3 is step-wise phosphorylated generating higher inositol polyphosphates (IP4-8) whose physiology remains poorly understood. In particular, inositol pyrophosphates (IP7/8) containing energetic pyrophosphate bond(s) are enigmatic inositol derivatives dynamically generated from inositol hexakisphosphate (IP6) by IP6 kinases (IP6Ks) and IP7 kinases (IP7Ks). We have previously uncovered IP7 as a critical determinant of cancer cell fate (apoptosis vs metastasis). By studying the regulation of IP6Ks and enzymes leading to IP6 production in cell- and animal-based models, we aim to uncover the (patho)physiology (e.g. cell migration and cancer metastasis) and signal transduction pathways mediated by inositol pyrophosphate metabolites, especially in the context of disease microenviroments. On top of this, we employ chemical and biochemical approaches to identify effector modules and their mode of interactions, with the goal to unravel underlying principles of inositol pyrophosphate signaling. Given the key roles of IP6K/IP7 in tumor progression and other metabolic diseases, the mechanistic and functional insights gained from this investigation will hopefully provide new therapeutic targets.

2. Cullin RING ligases and protein (de)Neddylation (Fig 2)

Cullin Ring E3 ligases(CRLs) are a major family of protein ubiquitination

Machineries that are aberrantly active in cancer and mediate the degradation of many proteins involved in carcinogenic process such as cell survival, growth, metabolism, autophagy, migration and immune evasion. Neddylation activates CRL. The COP9 signalosome (CSN) binds, deneddylates, and inactivates CRL. Our group recently discovered a role for the inositol polyphosphate metabolites in assembling and disassembling CRL-CSN complexes. How such metabolite-dependent CRL regulation integrates into cellular physiology, especially in context of nutrient sensing, is the emphasis of our future studies.


Teaching

Biochemistry II (Metabolism), Molecular Pharmacology, Frontier in Life Sciences Seminar


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Research Achievements

(1)Identified IP6 as a CRL-CSN intermolecular “glue” that regulates CRL neddylation and activity under various physiological settings(Rao et al. PNAS, 2014; Scherer,…,Rao*. PNAS, 2016; Lin,…, Rao*. PNAS 2020, Zhang,…, Rao*. JBC 2020, Lin,…, Rao*. Nat. Commun. 2021)

(2)Uncovered IP7  as a GPCR messenger (Zhang et al. Nat Metab, 2021) and a critical determinant of cancer cell fate (apoptosis vs metastasis).(Rao et al. Mol Cell, 2014, Rao et al. PNAS 2015)。

(3)First to identify the YybT family phosphodiesterases that specifically hydrolyzes the 2nd messenger c-di-AMP(Rao et al.JBC 2010, Rao et al. J. Bacteriol. 2011, Tan#, Rao# et al. JBC 2013).

(4)Invented a method for large-scale production of the 2nd messenger c-di-GMP by enzymatic synthesis(Patent:US8,859,237 B2; Rao et al. Anal. Biochem. 2009); Elucidated the catalytic and regulatory mechanisms of c-di-GMP specific phosphodiesterases (Rao et al. J. Bacteriol. 2008, Rao et al. J. Bacteriol. 2009;)。

News More

  • PNAS: Dr. Feng Rao's group identified the metabolite inositol hexakisphosphate as an intermolecular "glue" regulating Cullin RING ligases

    2020-02-22

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Join us

We have open positions for postdoctoral fellow and one for doctoral student . If you are interested, please contact us:

raof@sustech.edu.cn

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Contact Us

Contact Address

Room 324, Building B, Southern University of Science and Technology, No. 1088 Xueyuan Rd., Nanshan District, Shenzhen, Guangdong, China, 518055

Office Phone

0755-88018439

Email

raof@sustech.edu.cn

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