Myelination in the central nervous system (CNS) has a pivotal role in vertebrate brain function, but the process is only poorly understood at the molecular level. Recently, myelin-gene regulatory factor (MRF) has been shown to control the expression of a number of mouse CNS myelin genes, and its Dictyostelium orthologue MrfA was found to regulate prestalk cell differentiation. To better understand the molecular mechanism of MrfA function, Jeffrey Williams and colleagues (p. 5247) set out to further characterize this factor. They show that MrfA and animal MRFs contain a predicted trans-membrane domain – a feature of other membrane-tethered transcription factors that are activated by protease-mediated cleavage and subsequent release from the membrane. However, when the authors investigate the activation mechanism of MrfA, they find that, surprisingly, MrfA undergoes a form of constitutive auto-proteolytic cleavage, which thus far has only been described for the intramolecular chaperone domains (CICMDs) of bacteriophage tail-spike proteins. Thus the MRF domain of MrfA has extensive sequence identity to the CICMDs and utilizes the same serine-lysine dyad cleavage mechanism of auto-proteolysis. Interestingly, an identical cleavage mechanism has just been reported elsewhere for the vertebrate orthologues, suggesting that the phage approach to protein activation is either remarkably conserved in evolution or there has been lateral prokaryote–eukaryote domain transfer.