Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement
Open accessAbstract
Cul3, a Cullin family scaffold protein, is thought to mediate the assembly of a large number of SCF (Skp1-Cullin1-F-box protein)-like ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors. Cul3 controls early embryonic development in several genetic models through mechanisms not understood. Very few functional substrate/adaptor pairs for Cul3 ubiquitin ligases have been identified. Here, we show that Cul3 knockdown in human cells results in abnormal actin stress fibers and distorted cell morphology, owing to impaired ubiquitination and degradation of small GTPase RhoA. We identify a family of RhoA-binding BTB domain adaptors conserved from insects to mammals, designated BACURDs. BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Dysfunction of the Cul3/BACURD complex decreases cell migration potential and impairs RhoA-mediated convergent extension movements during Xenopus gastrulation. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.
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CUL3BACURD ubiquitinates only GDP-bound inactive RhoA.
“While SMURF1 ubiquitinates active GTP-bound RhoA on Lys6 and Lys7 targeting RhoA for proteasomal degradation [66,67], CUL3BACURD ubiquitinates only GDP-bound inactive RhoA [68,69].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [68]
In the passage headed “Targeting RhoA for Polyubiquitination by the Cul3/BACURD Ubiquitin Ligase Complex,” the paper reports robust ubiquitination of GDP-loaded RhoA. It describes GTP-loaded and Mg2+-free RhoA as much poorer substrates, not as substrates that cannot be ubiquitinated; therefore, “only” overstates the finding. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRhoA is ubiquitylated by three different E3 ubiquitin ligase complexes: SMURF1, SCFFBXL19, and CUL3BACURD.
“RhoA is ubiquitylated by three different E3 ubiquitin ligase complexes: the SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), SKP1-CUL1-F-box FBXL19 (SCFFBXL19), and the BTB/POZ domain-containing adaptor for CUL3-mediated RhoA degradation (CUL3BACURD) ligase complex.”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [68]
The Introduction reports that Cul3/BACURD complexes ubiquitinate RhoA and identifies Smurf1 as a previously known RhoA-targeting ubiquitin ligase. Our copy does not identify SCF–FBXL19 as a RhoA ubiquitin ligase, so it does not support the claim that all three listed complexes ubiquitinate RhoA. No page numbers are provided for these passages. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Cites
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BackgroundSequence and structural analysis of BTB domain proteins
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- Authors
- Chen, Y., Yang, Z., Meng, M., Zhao, Y., Dong, N., Yan, H., Liu, L., Ding, M., Peng, H. B., & Shao, F.
- Affiliations
- Peking University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Hong Kong University of Science and Technology (HK)
- National Institute of Biological Sciences, Beijing (CN)
- Corresponding author
- Shao, Feng
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 35
- Issue
- 6
- Pages
- 841-855
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2046256501
- Cited by
- 270
- References
- 6
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 11 · 2023: 19 · 2022: 14 · 2021: 17 · 2020: 22 · 2019: 20 · 2018: 16 · 2017: 22 · 2016: 21 · 2015: 16 · 2014: 13 · 2013: 18 · 2012: 22
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1451 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Ministry of Science and Technology of the People's Republic of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- CUL3, RhoA, SCF ubiquitin ligase, protein degradation, ubiquitination, stress fibers, actin cytoskeleton, cell migration, convergent extension, Xenopus gastrulation, early embryonic development, small GTPases
- MeSH terms
- Actins, Animals, Cell Movement, Drosophila melanogaster, HeLa Cells, Humans, Protein Processing, Post-Translational, Recombinant Proteins, Transfection, Xenopus, Conserved Sequence, Evolution, Molecular, rhoA GTP-Binding Protein, Stress Fibers, Drosophila Proteins, Xenopus Proteins, RNA Interference, Cullin Proteins, Multiprotein Complexes, Cell Shape, Gastrulation, Ubiquitination
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