E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins, and which plays a key role in reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress (By similarity). In response to endoplasmic reticulum stress, recruited to the endoplasmic reticulum membrane by DDRGK1, and mediates ufmylation of proteins such as RPN1 and RPL26/uL24, thereby promoting reticulophagy of endoplasmic reticulum sheets (By similarity). Ufmylation-dependent reticulophagy inhibits the unfolded protein response (UPR) via ERN1/IRE1-alpha (By similarity). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:25952549, PubMed:29461087, PubMed:30701081). Regulates inflammation in response to endoplasmic reticulum stress by promoting reticulophagy, leading to inhibit the activity of the NF-kappa-B transcription factor (By similarity). Mediates ufmylation of DDRGK1 and CDK5RAP3; the role of these modifications is however unclear: as both DDRGK1 and CDK5RAP3 act as substrate adapters for ufmylation, it is uncertain whether ufmylation of these proteins is a collateral effect or is required for ufmylation (By similarity). Catalyzes ufmylation of various subunits of the ribosomal complex or associated components, such as RPS3/uS3, RPS20/uS10, RPL10/uL16, RPL26/uL24 and EIF6 (PubMed:28575669). Anchors CDK5RAP3 in the cytoplasm, preventing its translocation to the nucleus which allows expression of the CCND1 cyclin and progression of cells through the G1/S transition (By similarity). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 (By similarity). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (By similarity). Required for hematopoietic stem cell function and hematopoiesis (PubMed:25952549). Required for cardiac homeostasis (PubMed:30354401). Interacts with DDRGK1 (via PCI domain) (By similarity). Interacts with UFC1 (By similarity). Interacts with RELA (By similarity). Interacts with TRIP4 (By similarity). Interacts with CDK5RAP3; the interaction is direct (PubMed:21494687, PubMed:30635284). Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (By similarity). Recruited to double-strand breaks by the MRE11-RAD50-NBN (MRN) complex following DNA damage. Ubiquitously expressed with higher expression in pancreatic islets and other secretory tissues (PubMed:20228063, PubMed:21494687). In the embryonic brain at 17 dpc, detected in Sox2-positive neural stem cells and in Slc1a3/GLAST-positive radial glia (PubMed:20531390). In perinatal brain, highly expressed in Slc1a3-positive Bergmann glia of the cerebellum (PubMed:20531390). Continues to be expressed in Bergmann glia of adult brain at 16 weeks (PubMed:20531390). Expressed in adult heart (PubMed:30354401). Highly expressed in the intestinal exocrine cells (PubMed:30701081). Up-regulated in hypertrophic hearts (at protein level). Ubiquitinated, leading to its degradation by the proteasome. Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome. Phosphorylated at Ser-462 by ATM, enhancing protein ligase activity and promoting ATM activation in a positive feedback loop. Embryonic lethality caused by impaired erythroid development (PubMed:25952549). Conditional deletion in adult mice results in severe anemia and cytopenia (PubMed:25952549). Cells show elevated endoplasmic reticulum stress and unfolded protein response in bone marrow cells and impaired autophagic degradation (PubMed:25952549). Conditional knockout in cardiomyocytes causes age-dependent cardiomyopathy and heart failure, characterized by elevated cardiac fetal gene expression, increased fibrosis, and impaired cardiac contractility (PubMed:30354401). When challenged with pressure overload, cardiac-specific knockout mice display greater hypertrophy, exacerbated fibrosis, and worsened cardiac contractility compared to wild-type mice counterparts (PubMed:30354401). Conditional knockout in adults causes a significant loss of both Paneth and goblet cells in intestine, which in turn results in dysbiotic microbiota and increased susceptibility to experimentally induced colitis (PubMed:30701081). Belongs to the UFL1 family. Extended N-terminus.