FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains
Summary
O-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established O-fucosylation of epidermal growth factor-like repeats by protein O-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of O-fucosylation on the elastin microfibril interface (EMI) domain of Multimerin-1 (MMRN1). Here, using AlphaFold2 screens, co-immunoprecipitation, enzymatic assays combined with mass spectrometric analysis and CRISPR-Cas9 knockouts, we demonstrate that FUT10 and FUT11, originally annotated in UniProt as α1,3-fucosyltransferases, are actually POFUTs responsible for modifying EMI domains; thus, we renamed them as POFUT3 and POFUT4, respectively. Like POFUT1/2, POFUT3/4 function in the endoplasmic reticulum, require folded domain structures for modification and participate in a non-canonical endoplasmic reticulum quality control pathway for EMI domain-containing protein secretion. This finding expands the O-fucosylation repertoire and provides an entry point for further exploration in this emerging field of O-fucosylation. © 2025. The Author(s).
| Authors | Hao H, Yuan Y, Ito A, Eberand BM, Tjondro H, Cielesh M, Norris N, Moreno CL, Maxwell JWC, Neely GG, Payne RJ, Kebede MA, Urbauer RJB, Passam FH, Larance M, Haltiwanger RS |
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| Journal | Nature chemical biology |
| Publication Date | 2025 Apr;21(4):598-610 |
| PubMed | 39775168 |
| PubMed Central | PMC11949838 |
| DOI | 10.1038/s41589-024-01815-x |