Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki; Rhee, David Y.; Connelly, Michele; Sviderskiy, Vladislav O.; Bhasin, Deepak K.; Chen, Yizhe; Ong, Su-Sien; Chai, Sergio C.; Goktug, Asli N.; Huang, Guochang; Monda, Julie K.; Low, Jonathan; Kim, Ho Shin; Paulo, João A.; Cannon, Joe R.; Shelat, Anang A.; Chen, Taosheng; Kelsall, Ian R.; Alpi, Arno F.; Pagala, Vishwajeeth; Wang, Xusheng; Peng, Junmin; Singh, Bhuvanesh; Harper, J. Wade; Schulman, Brenda A.; Guy, R. Kiplin

doi:10.1038/nchembio.2386

Cited by 89 publications

(179 citation statements)

References 60 publications

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“…The NatC Nt-acetylated Met-1 of the E2 enzyme UBC12 (human UBE2M) binds in a hydrophobic pocket in E3 DCN1 (human DCUN1D1) (Scott et al, 2011), and this type of interaction is common for mammalian NEDD8 ligation enzymes (Monda et al, 2013). This direct involvement of the Nt acetyl group in protein binding was recently antagonized by inhibitors with selectivity for the Nt acetyl pockets of DCN1 and DCN2 (Scott et al, 2017). Nt acetylation may also indirectly affect binding, such as for Sir3's binding to the nucleosome, in which the Nt acetylation dependency is explained by stabilization of a binding loop (Arnaudo et al, 2013;Yang et al, 2013).…”

Section: The Eukaryotic Nat Machinerymentioning

confidence: 99%

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

2019

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Section: The Eukaryotic Nat Machinerymentioning

confidence: 99%

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

2019

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“…Depending on the type of linkage, polyubiquitination can have various functions (1)(2)(3). Whereas, for example, Lys 48 -linked chains are known to target the substrate protein for proteasomal degradation via the 26S proteasome, Lys 63 -linked chains are associated with a variety of nonproteolytic functions, such as trafficking, DNA damage response, and NF-B signaling in innate and adaptive immunity.…”

Section: Constitutive Nf-b Signaling Represents a Hallmark Of Chronicmentioning

confidence: 99%

Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

Brenke

Popowicz

Schorpp

et al. 2018

Journal of Biological Chemistry

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Constitutive NF-κB signaling represents a hallmark of chronic inflammation and autoimmune diseases. The E3 ligase TNF receptor-associated factor 6 (TRAF6) acts as a key regulator bridging innate immunity, pro-inflammatory cytokines, and antigen receptors to the canonical NF-κB pathway. Structural analysis and point mutations have unraveled the essential role of TRAF6 binding to the E2-conjugating enzyme ubiquitin-conjugating enzyme E2 N (Ubc13 or UBE2N) to generate Lys-linked ubiquitin chains for inflammatory and immune signal propagation. Genetic mutations disrupting TRAF6-Ubc13 binding have been shown to reduce TRAF6 activity and, consequently, NF-κB activation. However, to date, no small-molecule modulator is available to inhibit the TRAF6-Ubc13 interaction and thereby counteract NF-κB signaling and associated diseases. Here, using a high-throughput small-molecule screening approach, we discovered an inhibitor of the TRAF6-Ubc13 interaction that reduces TRAF6-Ubc13 activity both and in cells. We found that this compound, C25-140, impedes NF-κB activation in various immune and inflammatory signaling pathways also in primary human and murine cells. Importantly, C25-140 ameliorated inflammation and improved disease outcomes of autoimmune psoriasis and rheumatoid arthritis in preclinical mouse models. Hence, the first-in-class TRAF6-Ubc13 inhibitor C25-140 expands the toolbox for studying the impact of the ubiquitin system on immune signaling and underscores the importance of TRAF6 E3 ligase activity in psoriasis and rheumatoid arthritis. We propose that inhibition of TRAF6 activity by small molecules represents a promising novel strategy for targeting autoimmune and chronic inflammatory diseases.

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“…Previously, we reported a newly developed compound that specifically inhibits SCCRO and SCCRO2 activity by interfering with their interactions with UBC12 (25). This novel compound was used to screen for SCCRO-dependent, substrate-specific BTB-Kelch proteins that serve as adaptors in Cul3-anchored CRLs (25). Use of the inhibitor allowed the identification of binding interaction that acutely depends on the neddylation activity of SCCRO.…”

Section: Sccro Promotes Assembly Of Cul3 Klhl21 At the Midbodymentioning

confidence: 99%

Squamous cell carcinoma–related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission

Huang¹,

Kaufman²,

et al. 2017

Journal of Biological Chemistry

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Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation and Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody. The Cul3 adaptor KLHL21 mediates the effects of SCCRO on abscission, as it fails to localize to the midbody in SCCRO-deficient cells during abscission, and its inactivation resulted in phenotypic changes identical to SCCRO inactivation. Ubiquitination-promoted turnover of Aurora B at the midbody was deficient in SCCRO- and KLHL21-deficient cells, suggesting that it is the target of Cul3 at the midbody. Correction of abscission delays in SCCRO-deficient cells with addition of an Aurora B inhibitor at the midbody stage suggests that Aurora B is the target of SCCRO-promoted Cul3 activity. The activity of other Cul3-anchored complexes, including Cul3, was intact in SCCRO-deficient cells, suggesting that SCCRO selectively, rather than collectively, neddylates cullins Combined, these findings support a model in which the SCCRO, substrate, and substrate adaptors cooperatively provide tight control of neddylation and cullin-RING-ligase activity.

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Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

Cited by 89 publications

References 60 publications

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Targeting TRAF6 E3 ligase activity with a small-molecule inhibitor combats autoimmunity

Squamous cell carcinoma–related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission

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