UFC1 (ubiquitin-fold modifier conjugating enzyme 1) is an E2-like enzyme that catalyzes the second step of ufmylation, a ubiquitin-like post-translational modification pathway 1. UFC1 accepts the ubiquitin-like modifier UFM1 from the E1 enzyme UBA5 and forms a thioester intermediate with UFM1 via its catalytic cysteine residue (Cys116) 1. The ufmylation pathway, comprising UBA5 (E1), UFC1 (E2), UFL1 (E3), and UFM1, regulates diverse cellular processes including autophagy initiation, DNA damage response, interferon signaling, and mitotic spindle organization 234. Recent studies demonstrate that UFMylation facilitates VCP/p97-mediated autophagy by stabilizing BECN1 and promoting phosphatidylinositol-3-kinase complex assembly 2. Additionally, UFMylation promotes orthoflavivirus infectious particle production by regulating viral assembly mechanisms 4. Deficiency in UFMylation machinery components causes embryonic lethality in mice and human disease 5. UFC1 mutations have been genetically linked to neurodevelopmental disorders including microcephaly and neurodevelopmental disorder with spasticity and poor growth 36. The structural and catalytic mechanisms of UFC1 are conserved across metazoans, making it a critical component of cellular homeostasis 1.