Assembly of IMPDH2-Based, CTPS-Based, and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

Gerson Dierley Keppeke; S. John Calise; Edward K.L. Chan; Luis Eduardo C. Andrade

doi:10.1016/j.jgg.2015.04.002

Volume 42 Issue 6

Jun. 2015

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Article Navigation > Journal of Genetics and Genomics > 2015 > 42(6): 287-299

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Assembly of IMPDH2-Based, CTPS-Based, and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

doi: 10.1016/j.jgg.2015.04.002

a
Rheumatology Division, Federal University of Sao Paulo, Sao Paulo SP 04023-062, Brazil
b
Department of Oral Biology, University of Florida, Gainesville FL 32610-0424, USA
c
Immunology Division, Fleury Medicine and Health Laboratories, Sao Paulo SP 04102-050, Brazil

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Corresponding author: E-mail address: gerson.keppeke@gmail.com (Gerson Dierley Keppeke); E-mail address: luis.andrade@unifesp.br (Luis Eduardo C. Andrade)
Received Date: 2014-11-30
Accepted Date: 2015-04-09
Rev Recd Date: 2015-04-07

Available Online: 2015-04-18

Publish Date: 2015-06-20

Abstract

Abstract

Inhibition of guanosine triphosphate (GTP) and cytidine triphosphate (CTP) biosynthetic pathways induces cells to assemble rod/ring (RR) structures, also named cytoophidia, which consist of the enzymes cytidine triphosphate synthase (CTPS) and inosine-5′-monophosphate dehydrogenase 2 (IMPDH2). We aim to explore the interaction of CTPS and IMPDH2 in the generation of RR structures. HeLa and COS-7 cells were cultured in normal conditions or in the presence of 6-diazo-5-oxo-L-norleucine (DON), ribavirin, or mycophenolic acid (MPA). Over 90% of DON-treated cells presented RR structures. In HeLa cells, 35% of the RR structures were positive for IMPDH2 alone, 26% were CTPS alone, and 31% were IMPDH2/CTPS mixed, while in COS-7 cells, 42% of RR were IMPDH2 alone, 41% were CTPS alone, and 10% were IMPDH2/CTPS mixed. Ribavirin and MPA treatments induced only IMPDH2-based RR. Cells were also transfected with an N-terminal hemagglutinin (NHA)-tagged CTPS1 construct. Over 95% of NHA-CTPS1 transfected cells with DON treatment presented IMPDH2-based RR and almost 100% presented CTPS1-based RR; when treated with ribavirin, over 94% of transfected cells presented IMPDH2-based RR and 37% presented CTPS1-based RR, whereas 2% of untreated transfected cells presented IMPDH2-based RR and 28% presented CTPS1-based RR. These results may help in understanding the relationship between CTP and GTP biosynthetic pathways, especially concerning the formation of filamentous RR structures.
- Nucleotide synthesis,
- Enzyme aggregation,
- Enzyme inhibition,
- IMPDH2,
- CTPS

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References(34)

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