G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival.
Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histon...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-10-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011731&type=printable |
| _version_ | 1797394698215620608 |
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| author | Praveen Prakhar Bharat Bhatt Gaurav Kumar Lohia Awantika Shah Tanushree Mukherjee Ullas Kolthur-Seetharam Nagalingam R Sundaresan Raju S Rajmani Kithiganahalli Narayanaswamy Balaji |
| author_facet | Praveen Prakhar Bharat Bhatt Gaurav Kumar Lohia Awantika Shah Tanushree Mukherjee Ullas Kolthur-Seetharam Nagalingam R Sundaresan Raju S Rajmani Kithiganahalli Narayanaswamy Balaji |
| author_sort | Praveen Prakhar |
| collection | DOAJ |
| description | Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6-/- mice or in vivo infection in haplo-insufficient Sirt6-/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival. |
| first_indexed | 2024-03-09T00:23:31Z |
| format | Article |
| id | doaj.art-9d8f39d3d9084b8a940310936055e403 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-09T00:23:31Z |
| publishDate | 2023-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-9d8f39d3d9084b8a940310936055e4032023-12-12T05:32:24ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-10-011910e101173110.1371/journal.ppat.1011731G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival.Praveen PrakharBharat BhattGaurav Kumar LohiaAwantika ShahTanushree MukherjeeUllas Kolthur-SeetharamNagalingam R SundaresanRaju S RajmaniKithiganahalli Narayanaswamy BalajiCholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6-/- mice or in vivo infection in haplo-insufficient Sirt6-/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011731&type=printable |
| spellingShingle | Praveen Prakhar Bharat Bhatt Gaurav Kumar Lohia Awantika Shah Tanushree Mukherjee Ullas Kolthur-Seetharam Nagalingam R Sundaresan Raju S Rajmani Kithiganahalli Narayanaswamy Balaji G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. PLoS Pathogens |
| title | G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. |
| title_full | G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. |
| title_fullStr | G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. |
| title_full_unstemmed | G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. |
| title_short | G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival. |
| title_sort | g9a and sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011731&type=printable |
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