Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2.
Mycobacterium tuberculosis (Mtb) employs multiple strategies to evade host immune responses and persist within macrophages. We have previously shown that the cell envelope-associated Mtb serine hydrolase, Hip1, prevents robust macrophage activation and dampens host pro-inflammatory responses, allowi...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-05-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC4022732?pdf=render |
| _version_ | 1811208522424123392 |
|---|---|
| author | Jacqueline L Naffin-Olivos Maria Georgieva Nathan Goldfarb Ranjna Madan-Lala Lauren Dong Erica Bizzell Ethan Valinetz Gabriel S Brandt Sarah Yu Daniil E Shabashvili Dagmar Ringe Ben M Dunn Gregory A Petsko Jyothi Rengarajan |
| author_facet | Jacqueline L Naffin-Olivos Maria Georgieva Nathan Goldfarb Ranjna Madan-Lala Lauren Dong Erica Bizzell Ethan Valinetz Gabriel S Brandt Sarah Yu Daniil E Shabashvili Dagmar Ringe Ben M Dunn Gregory A Petsko Jyothi Rengarajan |
| author_sort | Jacqueline L Naffin-Olivos |
| collection | DOAJ |
| description | Mycobacterium tuberculosis (Mtb) employs multiple strategies to evade host immune responses and persist within macrophages. We have previously shown that the cell envelope-associated Mtb serine hydrolase, Hip1, prevents robust macrophage activation and dampens host pro-inflammatory responses, allowing Mtb to delay immune detection and accelerate disease progression. We now provide key mechanistic insights into the molecular and biochemical basis of Hip1 function. We establish that Hip1 is a serine protease with activity against protein and peptide substrates. Further, we show that the Mtb GroEL2 protein is a direct substrate of Hip1 protease activity. Cleavage of GroEL2 is specifically inhibited by serine protease inhibitors. We mapped the cleavage site within the N-terminus of GroEL2 and confirmed that this site is required for proteolysis of GroEL2 during Mtb growth. Interestingly, we discovered that Hip1-mediated cleavage of GroEL2 converts the protein from a multimeric to a monomeric form. Moreover, ectopic expression of cleaved GroEL2 monomers into the hip1 mutant complemented the hyperinflammatory phenotype of the hip1 mutant and restored wild type levels of cytokine responses in infected macrophages. Our studies point to Hip1-dependent proteolysis as a novel regulatory mechanism that helps Mtb respond rapidly to changing host immune environments during infection. These findings position Hip1 as an attractive target for inhibition for developing immunomodulatory therapeutics against Mtb. |
| first_indexed | 2024-04-12T04:22:50Z |
| format | Article |
| id | doaj.art-ee25a6671c85440f91e045389fbd1621 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-12T04:22:50Z |
| publishDate | 2014-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-ee25a6671c85440f91e045389fbd16212022-12-22T03:48:10ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-05-01105e100413210.1371/journal.ppat.1004132Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2.Jacqueline L Naffin-OlivosMaria GeorgievaNathan GoldfarbRanjna Madan-LalaLauren DongErica BizzellEthan ValinetzGabriel S BrandtSarah YuDaniil E ShabashviliDagmar RingeBen M DunnGregory A PetskoJyothi RengarajanMycobacterium tuberculosis (Mtb) employs multiple strategies to evade host immune responses and persist within macrophages. We have previously shown that the cell envelope-associated Mtb serine hydrolase, Hip1, prevents robust macrophage activation and dampens host pro-inflammatory responses, allowing Mtb to delay immune detection and accelerate disease progression. We now provide key mechanistic insights into the molecular and biochemical basis of Hip1 function. We establish that Hip1 is a serine protease with activity against protein and peptide substrates. Further, we show that the Mtb GroEL2 protein is a direct substrate of Hip1 protease activity. Cleavage of GroEL2 is specifically inhibited by serine protease inhibitors. We mapped the cleavage site within the N-terminus of GroEL2 and confirmed that this site is required for proteolysis of GroEL2 during Mtb growth. Interestingly, we discovered that Hip1-mediated cleavage of GroEL2 converts the protein from a multimeric to a monomeric form. Moreover, ectopic expression of cleaved GroEL2 monomers into the hip1 mutant complemented the hyperinflammatory phenotype of the hip1 mutant and restored wild type levels of cytokine responses in infected macrophages. Our studies point to Hip1-dependent proteolysis as a novel regulatory mechanism that helps Mtb respond rapidly to changing host immune environments during infection. These findings position Hip1 as an attractive target for inhibition for developing immunomodulatory therapeutics against Mtb.http://europepmc.org/articles/PMC4022732?pdf=render |
| spellingShingle | Jacqueline L Naffin-Olivos Maria Georgieva Nathan Goldfarb Ranjna Madan-Lala Lauren Dong Erica Bizzell Ethan Valinetz Gabriel S Brandt Sarah Yu Daniil E Shabashvili Dagmar Ringe Ben M Dunn Gregory A Petsko Jyothi Rengarajan Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. PLoS Pathogens |
| title | Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. |
| title_full | Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. |
| title_fullStr | Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. |
| title_full_unstemmed | Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. |
| title_short | Mycobacterium tuberculosis Hip1 modulates macrophage responses through proteolysis of GroEL2. |
| title_sort | mycobacterium tuberculosis hip1 modulates macrophage responses through proteolysis of groel2 |
| url | http://europepmc.org/articles/PMC4022732?pdf=render |
| work_keys_str_mv | AT jacquelinelnaffinolivos mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT mariageorgieva mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT nathangoldfarb mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT ranjnamadanlala mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT laurendong mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT ericabizzell mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT ethanvalinetz mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT gabrielsbrandt mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT sarahyu mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT daniileshabashvili mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT dagmarringe mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT benmdunn mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT gregoryapetsko mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 AT jyothirengarajan mycobacteriumtuberculosiship1modulatesmacrophageresponsesthroughproteolysisofgroel2 |