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

Publication date: 10 January 2017
Source:Cell Reports, Volume 18, Issue 2
Author(s): Khian Hong Pua, Dylan T. Stiles, Mathew E. Sowa, Gregory L. Verdine
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.

Graphical abstract

Teaser

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.


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