Deficiency of Murine UFM1-Specific E3 Ligase Causes Microcephaly and Inflammation

The UFM1 conjugation system is a Ubiquitin (Ub)-like modification system that is essential for animal development and normal physiology of multiple tissues and organs. It consists of UFM1, a Ub-like modifier, and the UFM1-specific enzymes (namely E1 enzyme UBA5, E2 enzyme UFC1 E2, and E3 ligases) that catalyze conjugation of UFM1 to its specific protein targets. Clinical studies have identified rare genetic variants in human UFM1, UBA5 and UFC1 genes that were linked to early-onset encephalopathy and defective brain development, strongly suggesting the critical role of the UFM1 system in the nervous system. Yet, the physiological function of this system in adult brain remains not defined. In this study, we investigated the role of UFM1 E3 ligase in adult mouse and found that both UFL1 and UFBP1 proteins, two components of UFM1 E3 ligase, are essential for survival of mature neurons in adult mouse. Neuron-specific deletion of either UFL1 or UFBP1 led to significant neuronal loss and elevation of inflammatory response. Interestingly, loss of one allele of UFBP1 genes caused the occurrence of seizure-like events. Our study has provided genetic evidence for the indispensable role of UFM1 E3 ligase in mature neurons and further demonstrated the importance of the UFM1 system in the nervous system.