Tumor Signaling & Angiogenesis Program


Honglin Li

Honglin Li, PhD


Cancer Immunology, Inflammation and Tolerance Program
Associate Professor of Biochemistry and Molecular Biology

 



Georgia Cancer Center
1410 Laney Walker Blvd., CN 2176
Office: 706-721-6143
Lab: 706-721-6154
hli@augusta.edu

Research Summary

My laboratory research is focused on a novel form of biochemical modification of proteins, namely the Ufmylation pathway. We are interested in elucidating its biological functions, investigating its molecular mechanisms and exploring its potential roles in the pathogenesis and treatment of various human diseases including cancer.

Research Interests

The Ufm1 conjugation system:

The Ufm1 (Ubiquitin-fold modifier 1) conjugation system is a novel ubiquitin (Ub)-like system that consists of Ufm1-specific E1 enzyme (Uba5), E2 enzyme (Ufc1), and E3 ligase(s). Similar to other Ub-like systems such as SUMO, the Ufm1 system promotes ufmylation (covalent modification by Ufm1) of target proteins through a series of enzymatic reactions catalyzed by E1, E2 and E3. However, very few targets have been identified so far. Multiple lines of evidence indicate its involvement in the pathogenesis of various human diseases, including neurological disorders, hematopoietic diseases, diabetes, ischemic heart injury, atherosclerosis and cancer. Interestingly, several bi-allelic mutations of Uba5 genes have been identified to be linked to early-onset encephalopathy and recessive cerebellar ataxia. Ufbp1, a component of Ufm1 E3 ligase, was also identified as a new genetic risk locus in Parkinson’s disease, but its biological function remains poorly understood.

Ufl1/Ufbp1 protein complex: a Ufm1-specific E3 ligase

We have identified a novel protein complex including Ufl1 (Ufm1 ligase 1, also known as RCAD, NLBP, Maxer and KIAA0776), Ufbp1 (Ufm1 binding protein 1, also designated as DDRGK1, Dashurin and C20orf116) that was subsequently identified as a putative Ufm1 E3 ligase. In an attempt to elucidate the biological functions of these proteins, we have recently created knockout mouse models of Ufl1 and Ufbp1 and demonstrated that both Ufl1 and Ufbp1 are essential for embryonic development and hematopoiesis. We are currently investigating its role in intestinal homeostasis and blood cell development, respectively. In collaboration with other MCG laboratories, we are also interested in its role in heart development and the immune system.

Recent Publications

  1. Li, H., Chelladurai, B. S., Zhang, K., Nicholson, A. W. (1993) Ribonuclease III cleavage of a bacteriophage T7 processing signal.  Divalent cation specificity, and specific anion effects.  Nucleic Acids Res. 21, 1919-1925.
  2. Li, H. and Nicholson, A. W. (1996) Defining the enzyme binding domain of a ribonuclease III processing signal. Ethylation interference and hydroxyl radical footprinting using catalytically inactive RNase III mutants. EMBO J. 15, 1421-1433.
  3. Li, H., Bergeron, L., Cryns, V., Pasternack, M. S., Zhu, H., Shi, L., Greenberg, A., Yuan, J. (1997) Activation of caspase-2 in apoptosis. Biol. Chem. 272, 21010-21017.
  4. Li, H., Zhu, H., Xu, C., Yuan, J. (1998) Cleavage of BID by caspase-8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501.
  5. Chou, J. J., Li, H., Salvesen, G., Yuan, J. and Wagner, G. (1999) Solution structure of Bid, an intracellular amplifier of apoptotic signaling. Cell 96, 615-624
  6. Li, H. and Yuan, J. (1999) Deciphering the pathways of life and death. Current Opinion in Cell Biology 11, 261-266.
  7. Tong, X. and Li, H. (2004) eNOS protects from prostate cancer cells from TRAIL-induced apoptosis. Cancer Letters 210, 63-71.
  8. Wu, J., Luo, S., Hai, J., Li, H. (2005) Mammalian CHORD-containing protein 1 is a novel heat shock protein 90-interacting protein. FEBS letters 579, 421-426.
  9. Jiang, H., Luo, S., Li, H. (2005) Cdk5 activator binding protein C53 regulates apoptosis induced by genotoxic stress via modulating cyclin B1 phosphorylation. Biol. Chem. 280, 20651-20659
  10. Yang, W., Monroe, J. Zhang, Y., George, D., Bremer, E, Li, H. (2006) Proteasome inhibition induces both pro-and anti-cell death pathways in prostate cancer cells. Cancer Letters 243, 217-227.
  11. Jiang, H., Wu, J., He, C., Yang, W., Li, H. (2009) A tumor suppressor C53 protein antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. Cell Research 19, 458-468.
  12. Wu, J., Lei, G., Mei, M, Li, H. (2010) A novel C53/LZAP-interacting protein regulates C53/LZAP stability and NF-kB signaling. Biol. Chem. 285, 15126-15136.
  13. Zhu, S., Zhang, J., Bai, G., Li, H. (2011) Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death and Diseases 2, e115.
  14. Zhang, Y., Zhang, M., Wu, J., Lei, G., Li, H. (2012) Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the endoplasmic reticulum homeostasis and inhibition of vesicle trafficking. PLoS One 7(11), e48587
  15. Wu, J., Jiang, H., Luo, S., Zhang, M., Zhang, Y., Sun, F., Huang, S., Li, H. (2013) Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture of the nuclear envelope. Cell Research 23, 691-704
  16. Zhang, M., Zhu, X., Zhang, Y., Cai, Y., Chen, J., Sivaprakasam, S., Gurav, A., Pi, W., Makala, L., Wu, J., Pace, B., Tuan-Lo, D., Ganapathy, V., Singh, N., Li, H. (2015) RCAD/Ufl1, an Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death and Differentiation.  22(12):1922-1934
  17. Cai, Y., Pi, W., Sivaprakasam, S., Zhu, X., Zhang, M., Chen, J., Makala, L., Lu, C., Wu, J., Teng, Y., Pace, B., Tuan, D., Singh, N., Li, H. (2015) UFBP1, a key component of the Ufm1 conjugation system, is essential for ufmylation-mediated regulation of erythroid development. PLoS Genetics 11(11):e1005643
  18. da Silva, S. R., Paiva, S., Bancerzb,M., Geletub,M., Lewisb,A., Chen, J., Cai, Y., Lukkarilac, J., Li,H., Gunning, P. (2016) A selective inhibitor of the UFM1-activating enzyme, UBA5. Med. Chem. Letters 2016 Sep 15;26(18):4542-7.
  19. Cai, Y., Singh, N. and Li, H. (2016) Essential role of Ufm1 conjugation in the hematopoietic system. Hematology 44(6):442-446. PMID: 27033164
  20. Miller, C., Cai, Y., Patton, T., Graves, S., Li, H., Sabbatini, M.E. (2016) RCAD/BiP Pathway is Necessary for the Proper Synthesis of Digestive Enzymes and the Secretory Function of the Exocrine Pancreas. Am. J. Physiol. Gastrointest. Liver Phsyiol. 312(3): G314-G326 (PMID: 28104585)

Funding

  • AHA/Greater Southeast Affiliate 16SDG30940002, 2016-2019
    “Role of Ufm1 conjugation in the heart”
  • NIH/NIDDK R01 (Pending, 2%)
    “Role of the Ufm1 E3 ligase in intestinal homeostasis”

Research Team

photo of Siyang Liu, PhD
Siyang Liu, PhD

Research Associate