Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV
Copyright © 2021 Nguyen, Nguyen, Zhao, Schank, Dang, Cao, Khanal, Chand Thakuri, Lu, Zhang, Li, Morrison, Wu, El Gazzar, Ning, Wang, Moorman and Yao..
T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Frontiers in immunology - 12(2021) vom: 27., Seite 601298 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Nguyen, Lam Ngoc Thao [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.06.2021 Date Revised 14.03.2023 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.3389/fimmu.2021.601298 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM323328342 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM323328342 | ||
| 003 | DE-627 | ||
| 005 | 20231226202810.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fimmu.2021.601298 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1077.xml |
| 035 | |a (DE-627)NLM323328342 | ||
| 035 | |a (NLM)33776993 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Nguyen, Lam Ngoc Thao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.06.2021 | ||
| 500 | |a Date Revised 14.03.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2021 Nguyen, Nguyen, Zhao, Schank, Dang, Cao, Khanal, Chand Thakuri, Lu, Zhang, Li, Morrison, Wu, El Gazzar, Ning, Wang, Moorman and Yao. | ||
| 520 | |a T cells are critical for the control of viral infections and T cell responses are regulated by a dynamic network of non-coding RNAs, including microRNAs (miR) and long non-coding RNAs (lncRNA). Here we show that an activation-induced decline of lncRNA growth arrest-specific transcript 5 (GAS5) activates DNA damage response (DDR), and regulates cellular functions and apoptosis in CD4 T cells derived from people living with HIV (PLHIV) via upregulation of miR-21. Notably, GAS5-miR21-mediated DDR and T cell dysfunction are observed in PLHIV on antiretroviral therapy (ART), who often exhibit immune activation due to low-grade inflammation despite robust virologic control. We found that GAS5 negatively regulates miR-21 expression, which in turn controls critical signaling pathways involved in DNA damage and cellular response. The sustained stimulation of T cells decreased GAS5, increased miR-21 and, as a result, caused dysfunction and apoptosis in CD4 T cells. Importantly, this inflammation-driven T cell over-activation and aberrant apoptosis in ART-controlled PLHIV and healthy subjects (HS) could be reversed by antagonizing the GAS5-miR-21 axis. Also, mutation of the miR-21 binding site on exon 4 of GAS5 gene to generate a GAS5 mutant abolished its ability to regulate miR-21 expression as well as T cell activation and apoptosis markers compared to the wild-type GAS5 transcript. Our data suggest that GAS5 regulates TCR-mediated activation and apoptosis in CD4 T cells during HIV infection through miR-21-mediated signaling. However, GAS5 effects on T cell exhaustion during HIV infection may be mediated by a mechanism beyond the GAS5-miR-21-mediated signaling. These results indicate that targeting the GAS5-miR-21 axis may improve activity and longevity of CD4 T cells in ART-treated PLHIV. This approach may also be useful for targeting other infectious or inflammatory diseases associated with T cell over-activation, exhaustion, and premature immune aging | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Gas5 | |
| 650 | 4 | |a HIV | |
| 650 | 4 | |a T cell dysregulation | |
| 650 | 4 | |a lncRNA | |
| 650 | 4 | |a miR-21 | |
| 650 | 7 | |a GAS5 long non-coding RNA, human |2 NLM | |
| 650 | 7 | |a MIRN21 microRNA, human |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a RNA, Long Noncoding |2 NLM | |
| 700 | 1 | |a Nguyen, Lam Nhat |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Juan |e verfasserin |4 aut | |
| 700 | 1 | |a Schank, Madison |e verfasserin |4 aut | |
| 700 | 1 | |a Dang, Xindi |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Dechao |e verfasserin |4 aut | |
| 700 | 1 | |a Khanal, Sushant |e verfasserin |4 aut | |
| 700 | 1 | |a Chand Thakuri, Bal Krishna |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Zeyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jinyu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhengke |e verfasserin |4 aut | |
| 700 | 1 | |a Morrison, Zheng D |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xiao Y |e verfasserin |4 aut | |
| 700 | 1 | |a El Gazzar, Mohamed |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Shunbin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Moorman, Jonathan P |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Zhi Q |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in immunology |d 2010 |g 12(2021) vom: 27., Seite 601298 |w (DE-627)NLM215811453 |x 1664-3224 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2021 |g day:27 |g pages:601298 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3389/fimmu.2021.601298 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2021 |b 27 |h 601298 | ||