IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex

• Published in: Cell reports (Cambridge) Vol. 18; no. 2; pp. 432 - 442
• Main Authors: Pua, Khian Hong, Stiles, Dylan T., Sowa, Mathew E., Verdine, Gregory L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-01-2017; Elsevier
• Subjects: Cell Proliferation; cyclophilin A; Cyclophilin A - metabolism; cystathionine-β-synthase domains; Humans; IMP Dehydrogenase - chemistry; IMP Dehydrogenase - metabolism; inosine-5′-monophosphate dehydrogenase; Jurkat Cells; K562 Cells; Lactones - chemistry; Lactones - metabolism; Protein Binding; Protein Domains; protein-protein interactions; sanglifehrin A; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Structure-Activity Relationship; sanglifehrin A; cyclophilin A; inosine-5′-monophosphate dehydrogenase; cystathionine-β-synthase domains; protein-protein interactions
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.030

Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5′-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2. Rather, ternary complex formation modulates cell growth through interaction with the cystathionine-β-synthase (CBS) domain of IMPDH2. We further demonstrate that the SFA complex is highly isoform selective for IMPDH2 (versus IMPDH1). This work reveals a role for the CBS domains of IMPDH2 in cellular proliferation, suggesting a more complex role than previously suspected for IMPDH2 in T cell activation and proliferation.
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•SFA engages IMPDH2 in a PPIA-dependent manner•PPIA-SFA interaction with IMPDH is highly isoform specific•PPIA-SFA complex binds the CBS domains of IMPDH2•CBS domains of IMPDH2 are implicated in cellular proliferation
Pua et al. identify IMPDH2 as an intracellular target of the PPIA-SFA complex and show that the CBS domains of IMPDH2 are required for cellular proliferation.