The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

Maitland, Matthew E. R.; Onea, Gabriel; Chiasson, Christopher A.; Wang, Xu; Ma, Jun; Moor, Sarah E; Barber, Kathryn R.; Lajoie, Gilles; Shaw, Gary S.; Schild-Poulter, Caroline

doi:10.1038/s41598-019-46279-5

Cited by 50 publications

(98 citation statements)

References 58 publications

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“…Nonetheless, so far the CTLH complex appears simpler than the human and yeast complexes. We were unable to identify orthologs of GID4 and GID5, which are seen in the human and yeast versions (Lampert et al, 2018;Maitland et al, 2019;Santt et al, 2008). Similarly, although WDR26 is important in the human complex and we identified a Drosophila ortholog (CG7611), we found no evidence of its association with ME31B or requirement for ME31B degradation.…”

Section: Discussioncontrasting

confidence: 62%

Egg activation triggers clearance of maternally deposited RNA binding proteins

Zavortink¹,

Rutt²,

Dzitoyeva³

et al. 2019

Preprint

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HIGHLIGHTS• Degradation of ME31B requires the PNG kinase, but not fertilization • The ubiquitin-proteasome system degrades ME31B via CTLH E3 ligase and the UBC-E2H/Kondo ubiquitin-conjugating enzyme• The association of ME31B with the CTLH complex does not require PNG activity• PNG kinase mediates the translational upregulation of Kondo at egg activation 3 SUMMARYThe maternal-to-zygotic transition (MZT) is a conserved step in animal development, where control is passed from the maternal genome to the zygotic one. Although the MZT is typically considered from its impact on the transcriptome, we previously found that three maternally deposited Drosophila RNA binding proteins (ME31B, Trailer Hitch[TRAL], and Cup) are also cleared during the MZT by unknown mechanisms. Here, weshow that these proteins are degraded by the ubiquitin-proteasome system. Kondo, an E2 conjugating enzyme, and the E3 CTLH ligase are required for the destruction of ME31B, TRAL, and Cup. Importantly, despite occurring hours earlier, egg activation establishes the timer for clearance of these proteins by activating the Pan Gu kinase, which in turn stimulates translation of Kondo mRNA. In other words, egg activation triggers a series of regulatory events that culminate in the degradation of maternally deposited RNA binding proteins several hours later. Clearance of the maternal protein dowry thus appears to be a coordinated, but as-yet underappreciated, aspect of the MZT. 4

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Section: Discussioncontrasting

confidence: 62%

Egg activation triggers clearance of maternally deposited RNA binding proteins

Zavortink¹,

Rutt²,

Dzitoyeva³

et al. 2019

Preprint

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“…Our previous report suggests that the GID complex is involved in the ubiquitination of β-Catenin and is independent of the Wnt signalling pathway 16 . Among the components of the GID complex, RMND5A and MAEA (mammalian homologues of yeast GID2 and GID9, respectively) encode E3 ubiquitin ligases [33][34][35] . We confirmed that RMND5A and MAEA ubiquitinated β-Catenin directly ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID

et al. 2020

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Abstractβ-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.

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“…Qiao et al (46) employed cryoelectron microscopy and other methods to characterize the entire GID Ub ligase, revealing its overall shape and also, in particular, specific interactions between its N-recognin subunit GID4 and the rest of GID. In mammals, the GID Ub ligase (it is also called CTLH) functions in primary cilia, in cell proliferation, and in other processes (96,(102)(103)(104)(105)(106)(107)(108)(109)(110).…”

Section: Significancementioning

confidence: 99%

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

Cheng

Chen

Melnykov³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Eukaryotic N-degron pathways are proteolytic systems whose unifying feature is their ability to recognize proteins containing N-terminal (Nt) degradation signals called N-degrons, and to target these proteins for degradation by the 26S proteasome or autophagy. GID4, a subunit of the GID ubiquitin ligase, is the main recognition component of the proline (Pro)/N-degron pathway. GID4 targets proteins through their Nt-Pro residue or a Pro at position 2, in the presence of specific downstream sequence motifs. Here we show that human GID4 can also recognize hydrophobic Nt-residues other than Pro. One example is the sequence Nt-IGLW, bearing Nt-Ile. Nt-IGLW binds to wild-type human GID4 with aKdof 16 μM, whereas the otherwise identical Nt-Pro–bearing sequence PGLW binds to GID4 more tightly, with aKdof 1.9 μM. Despite this difference in affinities of GID4 for Nt-IGLW vs. Nt-PGLW, we found that the GID4-mediated Pro/N-degron pathway of the yeastSaccharomyces cerevisiaecan target an Nt-IGLW–bearing protein for rapid degradation. We solved crystal structures of human GID4 bound to a peptide bearing Nt-Ile or Nt-Val. We also altered specific residues of human GID4 and measured the affinities of resulting mutant GID4s for Nt-IGLW and Nt-PGLW, thereby determining relative contributions of specific GID4 residues to the GID4-mediated recognition of Nt-Pro vs. Nt-residues other than Pro. These and related results advance the understanding of targeting by the Pro/N-degron pathway and greatly expand the substrate recognition range of the GID ubiquitin ligase in both human and yeast cells.

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The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation

Cited by 50 publications

References 58 publications

Egg activation triggers clearance of maternally deposited RNA binding proteins

Egg activation triggers clearance of maternally deposited RNA binding proteins

WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID

Recognition of nonproline N-terminal residues by the Pro/N-degron pathway

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