Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5
Abstract MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, there...
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| Veröffentlicht in: | Nucleic acids research 2023-10, Vol.51 (18), p.9849-9862 |
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| creator | Li, Chun Yoon, Bohyung Stefani, Giovanni Slack, Frank J |
| description | Abstract
MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.
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| doi_str_mv | 10.1093/nar/gkad709 |
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MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkad709</identifier><identifier>PMID: 37655623</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Active Transport, Cell Nucleus ; Animals ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans Proteins - genetics ; Caenorhabditis elegans Proteins - metabolism ; Humans ; Karyopherins - genetics ; Karyopherins - metabolism ; Lipids ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Molecular Biology ; Nuclear Proteins - metabolism ; Phosphotransferases (Alcohol Group Acceptor) - metabolism</subject><ispartof>Nucleic acids research, 2023-10, Vol.51 (18), p.9849-9862</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c371t-ae006269814e9a09855bf12b38198d219ade8e091fc02eaa828dadc15841b6f73</cites><orcidid>0000-0001-7809-7226</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570020/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10570020/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37655623$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Chun</creatorcontrib><creatorcontrib>Yoon, Bohyung</creatorcontrib><creatorcontrib>Stefani, Giovanni</creatorcontrib><creatorcontrib>Slack, Frank J</creatorcontrib><title>Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.
Graphical Abstract
Graphical Abstract</description><subject>Active Transport, Cell Nucleus</subject><subject>Animals</subject><subject>Caenorhabditis elegans - genetics</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Caenorhabditis elegans Proteins - genetics</subject><subject>Caenorhabditis elegans Proteins - metabolism</subject><subject>Humans</subject><subject>Karyopherins - genetics</subject><subject>Karyopherins - metabolism</subject><subject>Lipids</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>Molecular Biology</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc-L1DAUgIMo7rh68i45iSB130ubNj3JsPhjcXAHUfAW0va1E7dNapL647-3MuOiF085vI_vPfIx9hjhBUKdXzgTLoYb01VQ32EbzEuRFXUp7rIN5CAzhEKdsQcxfgHAAmVxn53lVSllKfINm3Z2th2_sc5E4vurvXyHWx5oWEaTKPKRUlbxybbBf3i_5Y31AzmKNvJ0CH4ZDty6RMG0ybqBf7fpwN3SjmQCpx-zD4nPwSeyjn_eX8uH7F5vxkiPTu85-_T61cfLt9nu-s3V5XaXtXmFKTMEUIqyVlhQbaBWUjY9iiZXWKtOYG06UgQ19i0IMkYJ1ZmuRakKbMq-ys_Zy6N3XpqJupZcCmbUc7CTCT-1N1b_O3H2oAf_TSPICkDAanh2MgT_daGY9GRjS-NoHPklaqFKKEBihSv6_IiufxRjoP52D4L-XUivhfSp0Eo_-fu0W_ZPkhV4egT8Mv_X9AtnXpuk</recordid><startdate>20231013</startdate><enddate>20231013</enddate><creator>Li, Chun</creator><creator>Yoon, Bohyung</creator><creator>Stefani, Giovanni</creator><creator>Slack, Frank J</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7809-7226</orcidid></search><sort><creationdate>20231013</creationdate><title>Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5</title><author>Li, Chun ; Yoon, Bohyung ; Stefani, Giovanni ; Slack, Frank J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c371t-ae006269814e9a09855bf12b38198d219ade8e091fc02eaa828dadc15841b6f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Active Transport, Cell Nucleus</topic><topic>Animals</topic><topic>Caenorhabditis elegans - genetics</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Caenorhabditis elegans Proteins - genetics</topic><topic>Caenorhabditis elegans Proteins - metabolism</topic><topic>Humans</topic><topic>Karyopherins - genetics</topic><topic>Karyopherins - metabolism</topic><topic>Lipids</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>Molecular Biology</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Chun</creatorcontrib><creatorcontrib>Yoon, Bohyung</creatorcontrib><creatorcontrib>Stefani, Giovanni</creatorcontrib><creatorcontrib>Slack, Frank J</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Chun</au><au>Yoon, Bohyung</au><au>Stefani, Giovanni</au><au>Slack, Frank J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2023-10-13</date><risdate>2023</risdate><volume>51</volume><issue>18</issue><spage>9849</spage><epage>9862</epage><pages>9849-9862</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
MicroRNAs (miRNAs) are small non-coding RNAs first discovered in Caenorhabditis elegans. The let-7 miRNA is highly conserved in sequence, biogenesis and function from C. elegans to humans. During miRNA biogenesis, XPO5-mediated nuclear export of pre-miRNAs is a rate-limiting step and, therefore, might be critical for the quantitative control of miRNA levels, yet little is known about how this is regulated. Here we show a novel role for lipid kinase PPK-1/PIP5K1A (phosphatidylinositol-4-phosphate 5-kinase) in regulating miRNA levels. We found that C. elegans PPK-1 functions in the lin-28/let-7 heterochronic pathway, which regulates the strict developmental timing of seam cells. In C. elegans and human cells, PPK-1/PIP5K1A regulates let-7 miRNA levels. We investigated the mechanism further in human cells and show that PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature miRNA levels by blocking the binding of XPO5 to pre-let-7 miRNA. Furthermore, we demonstrate that this role for PIP5K1A is kinase-independent. Our study uncovers the novel finding of a direct connection between PIP5K1A and miRNA biogenesis. Given that miRNAs are implicated in multiple diseases, including cancer, this new finding might lead to a novel therapeutic opportunity.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>37655623</pmid><doi>10.1093/nar/gkad709</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-7809-7226</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Active Transport, Cell Nucleus Animals Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Humans Karyopherins - genetics Karyopherins - metabolism Lipids MicroRNAs - genetics MicroRNAs - metabolism Molecular Biology Nuclear Proteins - metabolism Phosphotransferases (Alcohol Group Acceptor) - metabolism |
| title | Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5 |
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