Palmitoylation enables MAPK-dependent proteostasis of axon survival factors
Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-09, Vol.115 (37), p.E8746-E8754 |
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| creator | Summers, Daniel W. Milbrandt, Jeffrey DiAntonio, Aaron |
| description | Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival. |
| doi_str_mv | 10.1073/pnas.1806933115 |
| format | Article |
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Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1806933115</identifier><identifier>PMID: 30150401</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Armadillo Domain Proteins - metabolism ; Axons ; Axons - metabolism ; Biological Sciences ; Cell Survival - drug effects ; Cells, Cultured ; Cytoskeletal Proteins - metabolism ; Deactivation ; Degeneration ; Dismantling ; Fatty acids ; HEK293 Cells ; Homeostasis ; Humans ; Inactivation ; Kinases ; Leucine ; Leucine zipper proteins ; Lipoylation ; Localization ; MAP kinase ; MAP Kinase Kinase Kinases - antagonists & inhibitors ; MAP Kinase Kinase Kinases - metabolism ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - physiology ; Mice ; Nerve Degeneration - prevention & control ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Neurons - cytology ; Neurons - metabolism ; Neuroprotection ; Nicotinamide-Nucleotide Adenylyltransferase - metabolism ; Palmitoylation ; Pharmacology ; Piperazines - pharmacology ; PNAS Plus ; Proteins ; Proteostasis - physiology ; Survival ; Survival factor</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-09, Vol.115 (37), p.E8746-E8754</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Sep 11, 2018</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-c8b42b4d5aecd838a6272655fb4161a69f8e0544d876542829f41cff3e4ca7bf3</citedby><cites>FETCH-LOGICAL-c509t-c8b42b4d5aecd838a6272655fb4161a69f8e0544d876542829f41cff3e4ca7bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26531331$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26531331$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30150401$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Summers, Daniel W.</creatorcontrib><creatorcontrib>Milbrandt, Jeffrey</creatorcontrib><creatorcontrib>DiAntonio, Aaron</creatorcontrib><title>Palmitoylation enables MAPK-dependent proteostasis of axon survival factors</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival.</description><subject>Animals</subject><subject>Armadillo Domain Proteins - metabolism</subject><subject>Axons</subject><subject>Axons - metabolism</subject><subject>Biological Sciences</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Deactivation</subject><subject>Degeneration</subject><subject>Dismantling</subject><subject>Fatty acids</subject><subject>HEK293 Cells</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Kinases</subject><subject>Leucine</subject><subject>Leucine zipper proteins</subject><subject>Lipoylation</subject><subject>Localization</subject><subject>MAP kinase</subject><subject>MAP Kinase Kinase Kinases - antagonists & inhibitors</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mice</subject><subject>Nerve Degeneration - prevention & control</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurons</subject><subject>Neurons - cytology</subject><subject>Neurons - metabolism</subject><subject>Neuroprotection</subject><subject>Nicotinamide-Nucleotide Adenylyltransferase - metabolism</subject><subject>Palmitoylation</subject><subject>Pharmacology</subject><subject>Piperazines - pharmacology</subject><subject>PNAS Plus</subject><subject>Proteins</subject><subject>Proteostasis - physiology</subject><subject>Survival</subject><subject>Survival factor</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1P3DAQxS1EVba0Z05UkXrpJTDjj8S5ICHUL0FVDu3Zmjg2ZJWNUztZlf--RkuXtqc5vN88zbzH2AnCGUItzqeR0hlqqBohENUBWyE0WFaygUO2AuB1qSWXR-xVSmsAaJSGl-xIACqQgCt2fUvDpp_Dw0BzH8bCjdQOLhVfL2-vy85NbuzcOBdTDLMLaabUpyL4gn5lNi1x229pKDzZOcT0mr3wNCT35mkesx8fP3y_-lzefPv05eryprQKmrm0upW8lZ0iZzstNFW85pVSvpVYIVWN1w6UlJ2uKyW55o2XaL0XTlqqWy-O2cXOd1rajetsPjDSYKbYbyg-mEC9-VcZ-3tzF7amQgkKeTZ4_2QQw8_Fpdls-mTdMNDowpIMzzkpwbnUGX33H7oOSxzze4YjglS6kZCp8x1lY0gpOr8_BsE8FmUeizLPReWNt3__sOf_NJOB0x2wTjnbvZ6DEpgtxG-B35mH</recordid><startdate>20180911</startdate><enddate>20180911</enddate><creator>Summers, Daniel W.</creator><creator>Milbrandt, Jeffrey</creator><creator>DiAntonio, Aaron</creator><general>National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180911</creationdate><title>Palmitoylation enables MAPK-dependent proteostasis of axon survival factors</title><author>Summers, Daniel W. ; Milbrandt, Jeffrey ; DiAntonio, Aaron</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-c8b42b4d5aecd838a6272655fb4161a69f8e0544d876542829f41cff3e4ca7bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Armadillo Domain Proteins - metabolism</topic><topic>Axons</topic><topic>Axons - metabolism</topic><topic>Biological Sciences</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>Deactivation</topic><topic>Degeneration</topic><topic>Dismantling</topic><topic>Fatty acids</topic><topic>HEK293 Cells</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Kinases</topic><topic>Leucine</topic><topic>Leucine zipper proteins</topic><topic>Lipoylation</topic><topic>Localization</topic><topic>MAP kinase</topic><topic>MAP Kinase Kinase Kinases - antagonists & inhibitors</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mice</topic><topic>Nerve Degeneration - prevention & control</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurons</topic><topic>Neurons - cytology</topic><topic>Neurons - metabolism</topic><topic>Neuroprotection</topic><topic>Nicotinamide-Nucleotide Adenylyltransferase - metabolism</topic><topic>Palmitoylation</topic><topic>Pharmacology</topic><topic>Piperazines - pharmacology</topic><topic>PNAS Plus</topic><topic>Proteins</topic><topic>Proteostasis - physiology</topic><topic>Survival</topic><topic>Survival factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Summers, Daniel W.</creatorcontrib><creatorcontrib>Milbrandt, Jeffrey</creatorcontrib><creatorcontrib>DiAntonio, Aaron</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Summers, Daniel W.</au><au>Milbrandt, Jeffrey</au><au>DiAntonio, Aaron</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Palmitoylation enables MAPK-dependent proteostasis of axon survival factors</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-09-11</date><risdate>2018</risdate><volume>115</volume><issue>37</issue><spage>E8746</spage><epage>E8754</epage><pages>E8746-E8754</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Axon degeneration is a prominent event in many neurodegenerative disorders. Axon injury stimulates an intrinsic self-destruction program that culminates in activation of the prodegeneration factor SARM1 and local dismantling of damaged axon segments. In healthy axons, SARM1 activity is restrained by constant delivery of the axon survival factor NMNAT2. Elevating NMNAT2 is neuroprotective, while loss of NMNAT2 evokes SARM1-dependent axon degeneration. As a gatekeeper of axon survival, NMNAT2 abundance is an important regulatory node in neuronal health, highlighting the need to understand the mechanisms behind NMNAT2 protein homeostasis. We demonstrate that pharmacological inhibition of the MAP3Ks dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) elevates NMNAT2 abundance and strongly protects axons from injury-induced degeneration. We discover that MAPK signaling selectively promotes degradation of palmitoylated NMNAT2, as well as palmitoylated SCG10. Conversely, nonpalmitoylated NMNAT2 is degraded by the Phr1/Skp1a/Fbxo45 ligase complex. Combined inactivation of both pathways leads to synergistic accumulation of NMNAT2 in axons and dramatically enhanced protection against pathological axon degeneration. Hence, the subcellular localization of distinct pools of NMNAT2 enables differential regulation of NMNAT2 abundance to control axon survival.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30150401</pmid><doi>10.1073/pnas.1806933115</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Armadillo Domain Proteins - metabolism Axons Axons - metabolism Biological Sciences Cell Survival - drug effects Cells, Cultured Cytoskeletal Proteins - metabolism Deactivation Degeneration Dismantling Fatty acids HEK293 Cells Homeostasis Humans Inactivation Kinases Leucine Leucine zipper proteins Lipoylation Localization MAP kinase MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - metabolism MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - physiology Mice Nerve Degeneration - prevention & control Neurodegeneration Neurodegenerative diseases Neurons Neurons - cytology Neurons - metabolism Neuroprotection Nicotinamide-Nucleotide Adenylyltransferase - metabolism Palmitoylation Pharmacology Piperazines - pharmacology PNAS Plus Proteins Proteostasis - physiology Survival Survival factor |
| title | Palmitoylation enables MAPK-dependent proteostasis of axon survival factors |
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