Cargando…
Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells
During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection-augmented transcription of gene...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474003/ https://www.ncbi.nlm.nih.gov/pubmed/32858341 http://dx.doi.org/10.1016/j.isci.2020.101454 |
_version_ | 1783579267105292288 |
---|---|
author | Gerbec, Zachary J. Hashemi, Elaheh Nanbakhsh, Arash Holzhauer, Sandra Yang, Chao Mei, Ao Tsaih, Shirng-Wern Lemke, Angela Flister, Michael J. Riese, Matthew J. Thakar, Monica S. Malarkannan, Subramaniam |
author_facet | Gerbec, Zachary J. Hashemi, Elaheh Nanbakhsh, Arash Holzhauer, Sandra Yang, Chao Mei, Ao Tsaih, Shirng-Wern Lemke, Angela Flister, Michael J. Riese, Matthew J. Thakar, Monica S. Malarkannan, Subramaniam |
author_sort | Gerbec, Zachary J. |
collection | PubMed |
description | During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection-augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent on the transcriptional coactivator PGC-1α. Using an Ncr1(Cre)-based conditional knockout mouse, we found that PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios. Lack of PGC-1α also significantly impaired the ability of NK cells to control B16F10 tumor growth in vivo, and subsequent gene expression analysis showed that PGC-1α mediates transcription required to maintain mitochondrial activity within the tumor microenvironment. Together, these data suggest that PGC-1α-dependent transcription of specific target genes is required for optimal NK cell function during the response to infection or tumor growth. |
format | Online Article Text |
id | pubmed-7474003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-74740032020-09-11 Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells Gerbec, Zachary J. Hashemi, Elaheh Nanbakhsh, Arash Holzhauer, Sandra Yang, Chao Mei, Ao Tsaih, Shirng-Wern Lemke, Angela Flister, Michael J. Riese, Matthew J. Thakar, Monica S. Malarkannan, Subramaniam iScience Article During an immune response, natural killer (NK) cells activate specific metabolic pathways to meet the increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection-augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent on the transcriptional coactivator PGC-1α. Using an Ncr1(Cre)-based conditional knockout mouse, we found that PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios. Lack of PGC-1α also significantly impaired the ability of NK cells to control B16F10 tumor growth in vivo, and subsequent gene expression analysis showed that PGC-1α mediates transcription required to maintain mitochondrial activity within the tumor microenvironment. Together, these data suggest that PGC-1α-dependent transcription of specific target genes is required for optimal NK cell function during the response to infection or tumor growth. Elsevier 2020-08-13 /pmc/articles/PMC7474003/ /pubmed/32858341 http://dx.doi.org/10.1016/j.isci.2020.101454 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Gerbec, Zachary J. Hashemi, Elaheh Nanbakhsh, Arash Holzhauer, Sandra Yang, Chao Mei, Ao Tsaih, Shirng-Wern Lemke, Angela Flister, Michael J. Riese, Matthew J. Thakar, Monica S. Malarkannan, Subramaniam Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title | Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title_full | Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title_fullStr | Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title_full_unstemmed | Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title_short | Conditional Deletion of PGC-1α Results in Energetic and Functional Defects in NK Cells |
title_sort | conditional deletion of pgc-1α results in energetic and functional defects in nk cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474003/ https://www.ncbi.nlm.nih.gov/pubmed/32858341 http://dx.doi.org/10.1016/j.isci.2020.101454 |
work_keys_str_mv | AT gerbeczacharyj conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT hashemielaheh conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT nanbakhsharash conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT holzhauersandra conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT yangchao conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT meiao conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT tsaihshirngwern conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT lemkeangela conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT flistermichaelj conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT riesematthewj conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT thakarmonicas conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells AT malarkannansubramaniam conditionaldeletionofpgc1aresultsinenergeticandfunctionaldefectsinnkcells |