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Ubiquitylation of the ER-Shaping Protein Lunapark via the CRL3KLHL12 Ubiquitin Ligase Complex

Yuniati L 1 , Lauriola A 2 , Gerritsen M 1 , Abreu S 1 , Ni E 3 , Tesoriero C 2 Show all authors , Onireti JO 2 , Low TY 4 , Heck AJR 5 , Vettori A 2 , Cardozo T 3 , Guardavaccaro D 6

Affiliations 

  • 1 Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands
  • 2 Department of Biotechnology, University of Verona, 37134 Verona, Italy
  • 3 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY 10016, USA
  • 4 UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
  • 5 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands; The Netherlands Proteomics Center, 3584 CH Utrecht, the Netherlands
  • 6 Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Biotechnology, University of Verona, 37134 Verona, Italy. Electronic address: daniele.guardavaccaro@univr.it
Cell Rep, 2020 05 19;31(7):107664.
PMID: 32433973 DOI: 10.1016/j.celrep.2020.107664

Abstract

Cullin-RING ligases (CRLs) control key cellular processes by promoting ubiquitylation of a multitude of soluble cytosolic and nuclear proteins. Subsets of CRL complexes are recruited and activated locally at cellular membranes; however, few CRL functions and substrates at these distinct cellular compartments are known. Here, we use a proteomic screen to identify proteins that are ubiquitylated at cellular membranes and found that Lunapark, an endoplasmic reticulum (ER)-shaping protein localized to ER three-way junctions, is ubiquitylated by the CRL3KLHL12 ubiquitin ligase. We demonstrate that Lunapark interacts with mechanistic target of rapamycin complex-1 (mTORC1), a central cellular regulator that coordinates growth and metabolism with environmental conditions. We show that mTORC1 binds Lunapark specifically at three-way junctions, and lysosomes, where mTORC1 is activated, make contact with three-way junctions where Lunapark resides. Inhibition of Lunapark ubiquitylation results in neurodevelopmental defects indicating that KLHL12-dependent ubiquitylation of Lunapark is required for normal growth and development.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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