UFL1 (E3 UFM1-protein ligase 1) — research notes

UniProt: O94874 (UFL1_HUMAN), 794 aa. HGNC:23039. Chromosome 6. Synonyms: Maxer, NLBP, RCAD, KIAA0776.

Step in the cascade

UFL1 is the E3 ligase of the UFM1 (ufmylation) cascade (E1=UBA5, E2=UFC1, E3=UFL1).
EC=2.3.2.- (transferase). It is the catalytic component of the UREL complex (UFL1 + DDRGK1 + CDK5RAP3).
- UniProt FUNCTION: "E3 protein ligase that mediates ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to lysine residues on target proteins."
- Non-canonical scaffold-type E3 that activates the E2 UFC1 for aminolysis PMID:36121123.
- DDRGK1 tethers UREL to the ER membrane; CDK5RAP3 is the third subunit.

Core biology

• Principal substrate RPL26/uL24 on 60S ribosomes PMID:30626644.
• Ribosome recycling / ER-RQC: mono-ufmylation of RPL26 weakens the 60S–SEC61 junction, promoting release/recycling of post-termination or stalled 60S subunits [PMID:38383785; PMID:38383789; PMID:37036982 "UFMylation of translocon-bound 60S subunits modulates the RTJ"]. Core BP = GO:0072344 rescue of stalled ribosome (recycling).
• Reticulophagy / ER stress: ufmylates CYB5R3 PMID:36543799, RPN1; drives ER-phagy.
• DNA-damage response: recruited to DSBs via NBN; ufmylates histone H4 and MRE11 to promote ATM activation [PMID:30886146; PMID:30783677]. Phosphorylated at Ser-462 by ATM (positive feedback).
• Other substrates: TP53/p53 (stabilization) PMID:32807901; PD-L1/CD274 PMID:36893266; PD-1/PDCD1 (immune regulation) PMID:38377992; P4HB PMID:35753586; SYVN1/HRD1 PMID:37795761; TRIP4/ASC1 PMID:25219498.

Localization

Principal site: ER membrane (extensive EXP/IDA evidence). Also cytoplasm/cytosol, nucleus and chromosome (DNA-damage). Mitochondrial outer membrane (PMID:20164180, single IDA) is at odds with the dominant ER picture — marked over-annotation.

Core function conclusion

Core MF: GO:0061666 UFM1 ligase activity (E3). Core BP: protein ufmylation (RPL26) supporting 60S recycling / ER-RQC. Many other roles (DNA damage, immune, reticulophagy, transcription) are downstream/non-core.