The NEDD4-binding protein N4BP1 degrades mRNA substrates through the coding sequence independent of nonsense-mediated decay
3′UTRs are recognized for their role in regulating mRNA turnover while the turnover of a specific group of mRNAs mediated by coding sequences (CDSs) remains poorly understood. N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study rev...
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creator | Zheng, Wen Guo, Jinjing Ma, Shuyan Sun, Rong Song, Yihua Chen, Yuanmeng Mao, Renfang Fan, Yihui |
description | 3′UTRs are recognized for their role in regulating mRNA turnover while the turnover of a specific group of mRNAs mediated by coding sequences (CDSs) remains poorly understood. N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study reveals that N4BP1 efficiently degrades its mRNA targets via CDS rather than the 3′-UTR. This CDS-dependent mRNA turnover mechanism appears to be a general feature of N4BP1, as evidenced by testing multiple mRNA substrates, such as Fos-C, Fos-B, Jun-B, and C-X-C motif chemokine ligand 1. Detailed mapping of the motif identified a crucial 33-nt (289–322) sequence near the 5′-end of Fos-C-CDS, where the presence of polyC is necessary for N4BP1-mediated degradation. Functional studies involving domain deletion and point mutations showed that both the K homology and N4BP1, YacP-like nuclease domains are essential for N4BP1 to restrict mRNA substrates. The function of N4BP1 in mRNA turnover is not dependent on nonsense-mediated decay as it efficiently restricts mRNA substrates even in cells deficient in UPF1, UPF3A, and UPF3B. Additionally, the function of N4BP1 is not reliant on LUC7L3 despite its known association with this protein. Our findings suggest that N4BP1 acts as an endoribonuclease to degrade mRNA substrates primarily through CDSs containing a C-rich motif. |
doi_str_mv | 10.1016/j.jbc.2024.107954 |
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N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study reveals that N4BP1 efficiently degrades its mRNA targets via CDS rather than the 3′-UTR. This CDS-dependent mRNA turnover mechanism appears to be a general feature of N4BP1, as evidenced by testing multiple mRNA substrates, such as Fos-C, Fos-B, Jun-B, and C-X-C motif chemokine ligand 1. Detailed mapping of the motif identified a crucial 33-nt (289–322) sequence near the 5′-end of Fos-C-CDS, where the presence of polyC is necessary for N4BP1-mediated degradation. Functional studies involving domain deletion and point mutations showed that both the K homology and N4BP1, YacP-like nuclease domains are essential for N4BP1 to restrict mRNA substrates. The function of N4BP1 in mRNA turnover is not dependent on nonsense-mediated decay as it efficiently restricts mRNA substrates even in cells deficient in UPF1, UPF3A, and UPF3B. 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N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study reveals that N4BP1 efficiently degrades its mRNA targets via CDS rather than the 3′-UTR. This CDS-dependent mRNA turnover mechanism appears to be a general feature of N4BP1, as evidenced by testing multiple mRNA substrates, such as Fos-C, Fos-B, Jun-B, and C-X-C motif chemokine ligand 1. Detailed mapping of the motif identified a crucial 33-nt (289–322) sequence near the 5′-end of Fos-C-CDS, where the presence of polyC is necessary for N4BP1-mediated degradation. Functional studies involving domain deletion and point mutations showed that both the K homology and N4BP1, YacP-like nuclease domains are essential for N4BP1 to restrict mRNA substrates. The function of N4BP1 in mRNA turnover is not dependent on nonsense-mediated decay as it efficiently restricts mRNA substrates even in cells deficient in UPF1, UPF3A, and UPF3B. 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Our findings suggest that N4BP1 acts as an endoribonuclease to degrade mRNA substrates primarily through CDSs containing a C-rich motif.</description><subject>C-rich motif</subject><subject>Fos-C</subject><subject>KH domain</subject><subject>N4BP1</subject><subject>nonsense-mediated mRNA decay</subject><subject>NYN domain</subject><issn>0021-9258</issn><issn>1083-351X</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9UU1rGzEQFaUhcdP8gF6Kjr2sq9Fq17v0UPLVNhDcUlLoTWilWVvGlhxpNxDy5zOu09BcKoSGQe89jd5j7B2IKQioP66mq85OpZCK-llbqVdsAqIpi7KC36_ZRAgJRSur5oi9yXklaKkWDtlR2VKtVT1hDzdL5PPLiwtVdD44HxZ8m-KAPvC5OvsB3OEiGYeZb37OT3keuzwkM1A_LFMcF0uqyG38w8x4O2KwyEkJt0hHGHjseYghI-1ig84T2ZGqNfdv2UFv1hlPnuox-_Xl8ub8W3H9_evV-el1YWULQ9E0WAllYFY2XVcpp3pn67pytXCdlSX0toVeilIpqQyiq2FWNVDP6JZgjSyP2ee97nbsaAJLUyWz1tvkNybd62i8fnkT_FIv4p0G8oj4DSl8eFJIkb6YB73x2eJ6bQLGMesSCCUqMpWgsIfaFHNO2D-_A0LvUtMrTanpXWp6nxpx3v874DPjb0wE-LQHINl05zHpbP3OaecT2kG76P8j_wibu6ki</recordid><startdate>20241102</startdate><enddate>20241102</enddate><creator>Zheng, Wen</creator><creator>Guo, Jinjing</creator><creator>Ma, Shuyan</creator><creator>Sun, Rong</creator><creator>Song, Yihua</creator><creator>Chen, Yuanmeng</creator><creator>Mao, Renfang</creator><creator>Fan, Yihui</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20241102</creationdate><title>The NEDD4-binding protein N4BP1 degrades mRNA substrates through the coding sequence independent of nonsense-mediated decay</title><author>Zheng, Wen ; Guo, Jinjing ; Ma, Shuyan ; Sun, Rong ; Song, Yihua ; Chen, Yuanmeng ; Mao, Renfang ; Fan, Yihui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c291t-88e504a1738bb54d4fdc665d60dbc231fc91f2034424aeed61758167dbc665823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>C-rich motif</topic><topic>Fos-C</topic><topic>KH domain</topic><topic>N4BP1</topic><topic>nonsense-mediated mRNA decay</topic><topic>NYN domain</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Wen</creatorcontrib><creatorcontrib>Guo, Jinjing</creatorcontrib><creatorcontrib>Ma, Shuyan</creatorcontrib><creatorcontrib>Sun, Rong</creatorcontrib><creatorcontrib>Song, Yihua</creatorcontrib><creatorcontrib>Chen, Yuanmeng</creatorcontrib><creatorcontrib>Mao, Renfang</creatorcontrib><creatorcontrib>Fan, Yihui</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Wen</au><au>Guo, Jinjing</au><au>Ma, Shuyan</au><au>Sun, Rong</au><au>Song, Yihua</au><au>Chen, Yuanmeng</au><au>Mao, Renfang</au><au>Fan, Yihui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The NEDD4-binding protein N4BP1 degrades mRNA substrates through the coding sequence independent of nonsense-mediated decay</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2024-11-02</date><risdate>2024</risdate><volume>300</volume><issue>12</issue><spage>107954</spage><pages>107954-</pages><artnum>107954</artnum><issn>0021-9258</issn><issn>1083-351X</issn><eissn>1083-351X</eissn><abstract>3′UTRs are recognized for their role in regulating mRNA turnover while the turnover of a specific group of mRNAs mediated by coding sequences (CDSs) remains poorly understood. N4BP1 is a critical inflammatory regulator in vivo with a molecular mechanism that is not yet clearly defined. Our study reveals that N4BP1 efficiently degrades its mRNA targets via CDS rather than the 3′-UTR. This CDS-dependent mRNA turnover mechanism appears to be a general feature of N4BP1, as evidenced by testing multiple mRNA substrates, such as Fos-C, Fos-B, Jun-B, and C-X-C motif chemokine ligand 1. Detailed mapping of the motif identified a crucial 33-nt (289–322) sequence near the 5′-end of Fos-C-CDS, where the presence of polyC is necessary for N4BP1-mediated degradation. Functional studies involving domain deletion and point mutations showed that both the K homology and N4BP1, YacP-like nuclease domains are essential for N4BP1 to restrict mRNA substrates. The function of N4BP1 in mRNA turnover is not dependent on nonsense-mediated decay as it efficiently restricts mRNA substrates even in cells deficient in UPF1, UPF3A, and UPF3B. 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subjects | C-rich motif Fos-C KH domain N4BP1 nonsense-mediated mRNA decay NYN domain |
title | The NEDD4-binding protein N4BP1 degrades mRNA substrates through the coding sequence independent of nonsense-mediated decay |
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