A SPOPL/Cullin-3 ubiquitin ligase complex regulates endocytic trafficking by targeting EPS15 at endosomes

Michaela Gschweitl, Anna Ulbricht, Christopher A Barnes, Radoslav I Enchev, Ingrid Stoffel-Studer, Nathalie Meyer-Schaller, Jatta Huotari, Yohei Yamauchi, Urs F Greber, Ari Helenius, Matthias Peter

Research output: Contribution to journalArticle (Academic Journal)peer-review

47 Citations (Scopus)
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Cullin-3 (CUL3)-based ubiquitin ligases regulate endosome maturation and trafficking of endocytic cargo to lysosomes in mammalian cells. Here, we report that these functions depend on SPOPL, a substrate-specific CUL3 adaptor. We find that SPOPL associates with endosomes and is required for both the formation of multivesicular bodies (MVBs) and the endocytic host cell entry of influenza A virus. In SPOPL-depleted cells, endosomes are enlarged and fail to acquire intraluminal vesicles (ILVs). We identify a critical substrate ubiquitinated by CUL3-SPOPL as EPS15, an endocytic adaptor that also associates with the ESCRT-0 complex members HRS and STAM on endosomes. Indeed, EPS15 is ubiquitinated in a SPOPL-dependent manner, and accumulates with HRS in cells lacking SPOPL. Together, our data indicates that a CUL3-SPOPL E3 ubiquitin ligase complex regulates endocytic trafficking and MVB formation by ubiquitinating and degrading EPS15 at endosomes, thereby influencing influenza A virus infection as well as degradation of EGFR and other EPS15 targets.

Original languageEnglish
Article numbere13841
Number of pages26
Publication statusPublished - 23 Mar 2016


  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • CUL3
  • EGFR
  • endocytosis
  • EPS15
  • Human
  • Influenza A virus


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