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<p><i>O</i>-Fucosylation plays crucial roles in various essential biological events. Alongside the well-established <i>O</i>-fucosylation of epidermal growth factor-like repeats by protein <i>O</i>-fucosyltransferase 1 (POFUT1) and thrombospondin type 1 repeats by POFUT2, we recently identified a type of <i>O</i>-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 <i>O</i>-fucosylation repertoire and provides an entry point for further exploration in this emerging field of <i>O</i>-fucosylation.</p><p></p>

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FUT10 and FUT11 are protein O-fucosyltransferases that modify protein EMI domains

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月7日

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  • Huilin Hao,
  • Youxi Yuan,
  • Atsuko Ito,
  • Benjamin M. Eberand,
  • Harry Tjondro,
  • Michelle Cielesh,
  • Nicholas Norris,
  • Cesar L. Moreno,
  • Joshua W. C. Maxwell,
  • G. Gregory Neely,
  • Richard J. Payne,
  • Melkam A. Kebede,
  • Ramona J. Bieber Urbauer,
  • Freda H. Passam,
  • Mark Larance,
  • Robert S. Haltiwanger

摘要

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.