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

ABSTRACT: N-terminal acetylation is an abundant modification influencing protein functions. Because ?80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation-dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl-amide-binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2-E3 ligases.

SUBMITTER: Scott DC

PROVIDER: S-EPMC5577376 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Scott Daniel C DC Hammill Jared T JT Min Jaeki J Rhee David Y DY Connelly Michele M Sviderskiy Vladislav O VO Bhasin Deepak D Chen Yizhe Y Ong Su-Sien SS Chai Sergio C SC Goktug Asli N AN Huang Guochang G Monda Julie K JK Low Jonathan J Kim Ho Shin HS Paulo Joao A JA Cannon Joe R JR Shelat Anang A AA Chen Taosheng T Kelsall Ian R IR Alpi Arno F AF Pagala Vishwajeeth V Wang Xusheng X Peng Junmin J Singh Bhuvanesh B Harper J Wade JW Schulman Brenda A BA Guy R Kip RK

Nature chemical biology 20170605 8

N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the ...[more]

PMID: 28581483

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Project description:The accessory protein ORF6 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key interferon (IFN) antagonist that strongly suppresses the production of primary IFN as well as the expression of IFN-stimulated genes. However, how host cells respond to ORF6 remains largely unknown. Our research of ORF6-binding proteins by pulldown revealed that E3 ligase components such as Cullin 4B (CUL4B), DDB1, and RBX1 are potential ORF6-interacting proteins. Further study found that the substrate recognition receptor PRPF19 interacts with CUL4B, DDB1, and RBX1 to form a CRL4B-based E3 ligase, which catalyzes ORF6 ubiquitination and subsequent degradation. Overexpression of PRPF19 promotes ORF6 degradation, releasing ORF6-mediated IFN inhibition, which inhibits SARS-CoV-2 replication. Moreover, we found that activation of CUL4B by the neddylation inducer etoposide alleviates lung lesions in a SARS-CoV-2 mouse infection model. Therefore, targeting ORF6 for degradation may be an effective therapeutic strategy against SARS-CoV-2 infection.IMPORTANCEThe cellular biological function of the ubiquitin-proteasome pathway as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. It is a powerful tool that host cells use to defend against viral infection. Some cellular proteins can function as restriction factors to limit viral infection by ubiquitin-dependent degradation. In this research, we identificated of CUL4B-DDB1-PRPF19 E3 Ubiquitin Ligase Complex can mediate proteasomal degradation of ORF6, leading to inhibition of viral replication. Moreover, the CUL4B activator etoposide alleviates disease development in a mouse infection model, suggesting that this agent or its derivatives may be used to treat infections caused by SARS-CoV-2. We believe that these results will be extremely useful for the scientific and clinic communities in their search for cues and preventive measures to combat the COVID-19 pandemic.

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

Publications

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

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