Andrey Zavialov, PhD
Academy Research Fellow
Turku Centre for Biotechnology
University of Turku
Two distinct enzymes of adenosine deaminase, ADA1 and ADA2, have been found in humans. Inherited mutations in ADA1 result in severe combined immunodeficiency (SCID). This observation led to extensive studies of the structure and function of this enzyme that have revealed its important role in lymphocyte activation. In contrast, the physiological role of ADA2 is unknown. ADA2 activity in serum is increased in various diseases in which monocytes/macrophages are activated. We have found that ADA2 is a heparin-binding protein. The enzyme was purified and identified as a member of a new class of adenosine deaminase related growth factors (ADGF). Biochemical data suggest that ADA2 may be active at sites of inflammation during hypoxia and in areas of tumor growth where the adenosine concentration is significantly elevated and the extracellular pH is low. We showed that ADA2 is secreted by monocytes undergoing differentiation into macrophages or dendritic cells, and that neutrophiles, NK cells, monocytes, B cells and Treg cells are likely the main target for ADA2. The recently solved structure of ADA2 allows us to establish the role of unique ADA2 domains in the enzyme’s interaction with its specific receptor. The presence of two different ADAs in humans and their interaction with adenosine receptors, which may affect their function, has largely been ignored due to a lack of knowledge and a dearth of research teams performing systematic studies of adenosine receptors together with ADAs. At the same time, clinical studies have shown that ADA2 is a very specific biological marker for common and life-threatening diseases such as HIV, tuberculosis and breast cancer. Recently, our collaborators from the NIH and a group from Israel have identified patients with mutations in the ADA2 gene. It was shown that ADA2 concentration in the plasma of these patients is reduced more than 10-fold compared to that in healthy subjects. Furthermore, these patients display multiple health problems, including early onset systemic inflammation, multiple ischemic strokes, and vasculitis. Interestingly, the symptoms of the ADA2-deficient patients are distinct from SCID patients with ADA1 deficiency. Although the absence of either functional ADA1 or ADA2 leads to disregulated immune function, the lack of one functional enzyme is not compensated for by the presence of the remaining enzyme, suggesting that ADA1 and ADA2 have distinct roles. Strikingly, in both reports, the patients that were homozygous for a common mutation in Gly47 had clear symptoms of polyarteritis nodosa vasculopathy (PAN). Therefore, this type of mutation in ADA2 would be the first known and well-characterized cause of PAN. Our studies will explore the possibility that ADA2 is an immunomodulatory protein, which may directly or indirectly affect immune responses against intracellular pathogens or tumor cell proliferation. Our goal is to establish the physiological role of ADA2 in inflammation and tumor immunity and to explore its therapeutic potential.
- Liu Chengqian, MS (graduate student, TU)
- Kaljas Yuliia, MD, ML (graduate student, TU)
- Rai Balwant, MFO (graduate student, ÅA)
- Maksym Skaldin, MS (graduate student, ÅA)
The Academy of Finland, CIMO
Selected Peer-reviewed Publications
*Kaljas, Y., *Liu, C., *Skaldyn, M., Wu, C., Zhou, Q., Lu, Y., Aksentijevich, I.,§Zavialov, A. V. (2016) Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell. Mol. Life Sci. (in press).
*Liu, C., *Skaldyn M., Wu, C., Lu, Y., §Zavialov, A.V. (2016). Development and application of a sandwich ELISA with hADA1 as a marker enzyme to study the effect of low levels of adenosine on cytokine secretion by activated monocytes. Scientific reports.6: 31370
Gonzalez Santiago, T., Zavialov, A., Saarela, J., Seppanen, M. Reed, A., Abraham, R., Gibson, L.(2015). Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa. JAMA Dermatology151:1230-4
Montfrans, van J., Zavialov, A., Zhou, Q. (2014). Mutant ADA2 in vasculopathies. N Engl. J Med. 371:480-1
Zhou, Q., Yang, D., Ombrello, A.K., Zavialov, A.V. at al. (2014). Intermittent Fever and Early-Onset Stroke Due to Mutations in ADA2. N Engl. J Med. 370, 911-20.
In news: Nature Genetics Medscape NIH site Hematology times
Zavialov, Ant. V., Yu, X., Spillmann, D., Lauvau, G., §Zavialov, And. V. (2010). The structural basis for the growth factor activity of human adenosine deaminase 2. J Biol. Chem. 285, 12367-77.
§Zavialov, And. V., Gracia, E., Glaichenhaus, N., Franco, R., Zavialov, Ant. V., Lauvau, G. (2010). Human adenosine deaminase 2 induces differentiation of monocytes to macrophages and stimulates proliferation of T helper cells and macrophages. J Leuk. Biol. 88, 279-290.
§Zavialov, A. V., and Engström, Å. (2005). Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochemical J 391, 51-57.
§Zavialov, A.V., Buckingham, R.H., and Ehrenberg, M. (2001). A posttermination ribosomal complex is the guanine nucleotide exchange factor for peptide release factor RF3. Cell 107, 115-124.
In news: Molecular Cell
§Zavialov, A.V., Mora, L., Buckingham, R.H., and Ehrenberg, M. (2002). Release of Peptide Promoted by the GGQ-Motif of Class 1 Release Factors Regulates the GTPase Activity of RF3. Molecular Cell 10, 789-798.
*Rawat, U.B.S., *Zavialov, A.V., Sengupta, J., Valle, M., Grassucci, R.A., Linde, J., Vestergaard, B., Ehrenberg, M. and Frank, J (2003) A cryo-electron microscopic study of ribosome-bound termination factor RF2. Nature 421,87-90.
†Klaholz, B.P., Pape, T.,. Zavialov, A.V., Myasnikov, A.G., Orlova, E.V., Vestergaard, B., Ehrenberg, M. and van Heel, M. (2003) Structure of the E. coli ribosomal termination complex with release factor 2. Nature 421, 90-94.
Pedersen, K., Zavialov, A., Pavlov, M., Elf, K., Gerdes, K. and Ehrenberg, M. (2003). The bacterial toxin RelE displays codon specific cleavage of mRNAs in the ribosomal A-site. Cell. 112, 131-140.
§Zavialov, A., and Ehrenberg, M. (2003) Peptidyl-tRNA regulates the GTPase activity of bacterial translation factors. Cell, 113, 113-22.
Valle, M., Zavialov, A., Sengupta, J., Rawat, U., Ehrenberg, M., and Frank, J. (2003) Locking and unlocking of ribosomal motions. Cell, 113, 123-34.
Valle, M., Zavialov, A., Li, W., Stagg, S., Sengupta, J., Nielsen, R., Nissen, P., Harvey, S., Ehrenberg, M., and Frank, J. (2003). Incorporation of Aminoacyl-tRNA into the Ribosome as Seen by Cryo-EM. Nat. Struct. Biol. 10, 899-906.
Zavialov, A. V., Hauryliuk, V. V., and Ehrenberg, M. (2005). Guanine nucleotide exchange on ribosome bound elongation factor EF-G initiates translocation of tRNAs. Journal of Biology (now BMC Biology) 4, 9.
Gao, N., Zavialov, A. V., Li, W., Sengupta, J., Valle, M., Gursky, R. P., Ehrenberg, M., and Frank, J. (2005). Mechanism for the Disassembly of the Post-termination Complex Inferred from Cryo-EM studies. Mol. Cell 18, 663-674.
Allen, G. S., Zavialov, A., Gursky, R., Ehrenberg, M., and Frank, J. (2005). The Solution Structure of a Translation Initiation Complex from Escherichia coli at 13.8 Å. Cell 121, 703-12
Hauryliuk, V. V., Zavialov, A. V., Kisselev L. L., and Ehrenberg, M. (2006) Class-1 release factor eRF1 promotes GTP binding by class-2 release factor eRF3. Biochimie. 88, 747-57.
Gao H, Zhou Z, Rawat U, Huang C, Bouakaz L, Wang C, Cheng Z, Liu Y, Zavialov A, Gursky R, Sanyal S, Ehrenberg M, Frank J, Song H. (2007) RF3 Induces Ribosomal Conformational Changes Responsible for Dissociation of Class I Release Factors. Cell. 129, 929-941.
§ corresponding author