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FUNCTION 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 various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy) (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:27351204, PubMed:30626644, PubMed:30783677, PubMed:32160526, PubMed:32807901, PubMed:35394863, PubMed:36121123, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37311461, PubMed:37595036, PubMed:37795761, PubMed:38377992, PubMed:38383785, PubMed:38383789). Catalyzes ufmylation of many protein, such as CD274/PD-L1, CDK5RAP3, CYB5R3, DDRGK1, EIF6, histone H4, MRE11, P4HB, PDCD1/PD-1, TRIP4, RPN1, RPS20/uS10, RPL10/uL16, RPL26/uL24, SYVN1/HRD1 and TP53/p53 (PubMed:20018847, PubMed:20531390, PubMed:25219498, PubMed:30783677, PubMed:30886146, PubMed:32160526, PubMed:35753586, PubMed:36543799, PubMed:36893266, PubMed:37036982, PubMed:37595036, PubMed:37795761, PubMed:38383785, PubMed:38383789). As part of the UREL complex, plays a key role in ribosome recycling by catalyzing mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane (PubMed:38383785, PubMed:38383789). Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum (PubMed:37036982, PubMed:37595036, PubMed:38383785, PubMed:38383789). Involved in reticulophagy in response to endoplasmic reticulum stress by mediating ufmylation of proteins such as CYB5R3 and RPN1, thereby promoting lysosomal degradation of ufmylated proteins (PubMed:23152784, PubMed:32160526, PubMed:36543799). Ufmylation in response to endoplasmic reticulum stress is essential for processes such as hematopoiesis, blood vessel morphogenesis or inflammatory response (PubMed:32050156). 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 (PubMed:20018847, PubMed:20531390). Acts as a negative regulator of T-cell activation by mediating ufmylation and stabilization of PDCD1/PD-1 (PubMed:38377992). Also involved in the response to DNA damage: recruited to double-strand break sites following DNA damage and mediates monoufmylation of histone H4 and ufmylation of MRE11 (PubMed:30783677, PubMed:30886146). Mediates ufmylation of TP53/p53, promoting its stability (PubMed:32807901). Catalyzes ufmylation of TRIP4, thereby playing a role in nuclear receptor-mediated transcription (PubMed:25219498). Required for hematopoietic stem cell function and hematopoiesis (By similarity).SUBUNIT Catalytic component of the UFM1 ribosome E3 ligase (UREL) complex, composed of UFL1, DDRGK1 and CDK5RAP3 (PubMed:20018847, PubMed:20164180, PubMed:20228063, PubMed:25219498, PubMed:32160526, PubMed:36121123, PubMed:36543799, PubMed:37595036, PubMed:38383785, PubMed:38383789). Interacts with E2-like enzyme UFC1 (PubMed:20018847, PubMed:30886146, PubMed:37988244, PubMed:38383789). Interacts with RELA (PubMed:20164180). Interacts with NBN; promoting recruitment to double-strand breaks following DNA damage (PubMed:30886146). Interacts (when phosphorylated) with YWHAG/14-3-3-gamma; sequestering UFL1 and preventing its association with PDCD1/PD-1 substrate (PubMed:38377992).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein BILF1; this interaction mediates MAVS UFMylation and subsequent routing from mitochondria to lysosomes.INTERACTION Recruited to double-strand breaks by the MRE11-RAD50-NBN (MRN) complex following DNA damage.ALTERNATIVE PRODUCTS Ubiquitously expressed, with a high expression in liver (at protein level) (PubMed:20018847). Low expression in several invasive hepatocellular carcinomas, such Hep-G2, Hep 3B2.1-7, HLE and PLC (PubMed:20018847).INDUCTION Up-regulated by thapsigargin (PubMed:23152784). Down-regulated in the failing hearts of patients with dilated cardiomyopathy (PubMed:23152784).PTM Ubiquitinated, leading to its degradation by the proteasome (PubMed:20164180). Interaction with CDK5RAP3 protects both proteins against ubiquitination and degradation via the proteasome (PubMed:20164180).PTM Phosphorylated at Ser-462 by ATM, enhancing protein ligase activity and promoting ATM activation in a positive feedback loop (PubMed:30886146). Phosphorylation at Thr-536 by AMPK promotes its interaction with YWHAG/14-3-3-gamma, thereby preventing UFL1 association with PDCD1/PD-1 substrate (PubMed:38377992).SIMILARITY Belongs to the UFL1 family.SEQUENCE CAUTION Contaminating sequence. Potential poly-A sequence.SEQUENCE CAUTION Extended N-terminus.
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