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EIF3H binds YAP1. 29 / 36
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"These results implicated that mutated EIF3H catalytic core (EIF3H DDQ/AAA ) or disrupted EIF3H-YAP binding (EIF3H YW/AA ) has no effect on eIF3 complex integrity, YAP mRNA binds to eIF3 complex."
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"We further attempted to address the effect on the upstream signaling that participate to modulate the EIF3H-YAP cascade in cancer status."
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"In addition, we anticipated to determining the clinical relevance for dysregulated EIF3H-YAP axis in breast tumor the lung metastasis using human breast cancer mouse metastasis model."
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"Thus, we asked whether these signals play a role in regulating the EIF3H-YAP axis."
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"As shown in xref and xref – xref , we found that the inhibitors for PI3K (LY294002), S6K1 (PF4708671), Src (dasatinib) and mTOR (rapamycin) block EIF3H Ser/Thr phosphorylation, EIF3H-YAP binding and EIF3H-governed YAP accumulation but no effect for EIF3H/EIF3A binding."
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"However, YW-AA (Trp119, Tyr140 to alanine) mutant of EIF3H, two residues known for binding between EIF3H and YAP, still bound to HAX1 (Supplementary Fig. 5b)."
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"To further determine the clinical relevance for dysregulated EIF3H-YAP axis in breast tumor lung metastasis, we have utilized both mouse and human breast cancer mouse metastasis models ( xref )."
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"In the primary tumor growth, while the loss of EIF3H decrease cell proliferation and tumor growth, overexpression of both wild-type and mutant EIF3H resulted in full recovery of tumor growth suggesting a minor effect of EIF3H-YAP on tumor growth ( xref – xref and xref – xref )."
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"To our surprise, we observed, while only overexpression of the wild-type EIF3H fully recapitulates lung metastasis, the expression of mutant EIF3H fails to restore lung metastasis, indicating that EIF3H-YAP axis is critical for EIF3H-driven tumor invasion and metastasis ( xref and xref )."
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"While we observed an increased interaction between EIF3H and YAP, there was no corresponding increase in EIF3H expression in obese mice or following treatment with adipocyte‐conditioned medium (Figure  3A; Figure S5A, Supporting Information), suggesting an alternative mechanism that promotes the EIF3H‐YAP interaction."
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"55 To comprehensively address the mechanism by which the interplay of OGT‐mediated YAP‐ GlcNAcylation and EIF3H‐mediated deubiquitylation regulates YAP stability control, we conducted structural modeling of the interaction between YAP, OGT, and EIF3H by integrated use of docking simulations followed by experimental validation."
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"Further, we conducted an in‐depth exploration into the molecular interactions between deubiquitinase EIF3H and YAP, elucidating the specific interaction site of YAP with and without O‐GlcNAcylation moiety on Thr83."
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"Immunoprecipitation (IP) and blotting experiments revealed that while ACM‐induced YAP O‐GlcNAcylation was partially reduced across all mutant groups, the ACM‐induced interaction between YAP and EIF3H was specifically abolished in the T83A mutant, but not in the S109A or T241A mutants (Figure S7E, Supporting Information)."
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"However, there was a notable increase in the interaction between EIF3H and YAP, suggesting an alternative regulatory crosstalk mechanism at play.YAP O‐GlcNAcylation has been established as a regulatory mechanism that modulates YAP phosphorylation, nuclear localization, and transcriptional activation by disrupting its interaction with the upstream kinase LATS1."
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"This, in turn, leads to increased O‐GlcNAcylation of YAP at threonine 83, which enhances the interaction between EIF3H and YAP."
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"Covalent glycan‐protein attachment was employed via Charming (https://www.charmm‐gui.org/) to elucidate the pivotal role of glycans in mediating the interaction between YAP and EIF3H, shedding light on their functional significance in molecular recognition and signaling pathways."
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"Trp119 and Tyr 140 on EIF3H directly interacted with the N-terminal region of YAP1, facilitating complex formation of EIF3H and YAP1 for YAP1 deubiquitylation."
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"Under oncogenic circumstances, EIF3H directly interacts with YAP and catalyzes the removal of poly-ubiquitin chain on YAP, resulting in YAP stabilization and its transactivation ( xref )."
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"The interaction between EIF3H and YAP was further validated both in endogenous and ectopically as well as in vitro GST/His pull-down assay ( xref & xref and xref )."
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"The identification of an interaction between EIF3H and YAP brings us a puzzle because EIF3H was previously thought as a member of the eIF3 complex involved in regulating protein translational initiation and elongation ( xref )."
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"We further observed, while EIF3H cofractionated with EIF3A in peak I (Fraction 2-4), EIF3H cofractionated with YAP in peak II (Fraction 8-12), suggesting the presence of two endogenous EIF3H complexes, one eIF3 complex and another EIF3H-YAP complex."
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"The co-IP experiments further confirmed the presence of EIF3H-YAP complex in vivo ( xref )."
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"In addition, the interaction between endogenous EIF3H and YAP in both cytosol and nucleus was further confirmed by confocal immunofluorescence and in situ Proximity Ligation Assay ( xref and xref )."
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"Altogether, our identification of the interaction between EIF3H and YAP followed by characterization suggests that YAP is a substrate for EIF3H."
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"The above analysis has indicated the importance of the N-terminal 14 amino acids on YAP and the amino acid stretch 34-146 on EIF3H in mediating the interaction between YAP and EIF3H. To further identify the pivotal amino acid residues in EIF3H responsible for recognition of YAP by EIF3H, we have further performed molecular docking simulations by homology modelling service iTASSER and Haddock ( xref – xref )."
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"To determine the impact of W119 and Y140 on EIF3H in mediating the interaction between EIF3H with YAP, we have engineered double point mutant EIF3H constructs replacing by alanine (W119A and Y140A), and further tested the impact of these point mutations of EIF3H on altering the ubiquitylation and degradation of the substrate YAP."
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"As shown in xref – xref , replacement of Trp119, Tyr140 alone or combine by alanines significantly destabilized EIF3H-binding to YAP, presumably due to the perturbation of the interfacial interactions between EIF3H and YAP ( xref ), and reduced the deubiquitylation capacity of EIF3H, which function same as the catalytic core mutant EIF3H DDQ/AAA ( xref )."
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"Our blast analysis further suggests the potential role for the four conserved proline residues in this region that facilitate the interaction between YAP and EIF3H ( xref )."
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"Mutated EIF3H catalytic core or disrupted EIF3H-YAP binding affect YAP expression independent on translation."
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