Y12C mutation disrupts IMPDH cytoophidia and alters cancer metabolism.

Abstract

Guanosine triphosphate (GTP) is a building block for DNA and RNA, and plays a pivotal role in various cellular functions, serving as an energy source, enzyme cofactor and a key component of signal transduction. The activity of the rate-limiting enzyme in de novo GTP synthesis, inosine monophosphate dehydrogenase (IMPDH), is regulated by nucleotide binding. Recent studies have illuminated that IMPDH octamers can assemble into linear polymers, adding another dimension to its enzymatic regulation. This polymerisation reduces IMPDH's sensitivity to the inhibitory effects of GTP binding, thereby augmenting its activity under conditions with elevated GTP levels. Within cells, IMPDH polymers may cluster to form the distinctive structure known as the cytoophidium, which is postulated to reflect the cellular demand for increased GTP concentrations. Nevertheless, the functional significance of IMPDH polymerisation in in vivo metabolic regulation remains unclear. In this study, we report the widespread presence of IMPDH cytoophidia in various human cancer tissues. Utilising the ABEmax base editor, we introduced a Y12C point mutation into IMPDH2 across multiple cancer cell lines. This mutation disrupts the polymerisation interface of IMPDH and prevents cytoophidium assembly. In some cancer xenografts, the absence of IMPDH polymers led to a downregulation of IMPDH, as well as the glycolytic and pentose phosphate pathways. Furthermore, mutant HeLa-cell-derived xenografts were notably smaller than their wild-type counterparts. Our data suggest that IMPDH polymerisation and cytoophidium assembly could be instrumental in modulating metabolic homeostasis in certain cancers, offering insights into the clinical relevance of IMPDH cytoophidium.