A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants
Recent studies have linked necrotic cell death and proteolysis of inflammatory proteins to the adaptive immune response mediated by the lysosome-destabilizing adjuvants, alum and Leu-Leu-OMe (LLOMe). However, the mechanism by which lysosome-destabilizing agents trigger necrosis and proteolysis of inflammatory proteins is poorly understood. The proteasome is a cellular complex that has been shown to regulate both necrotic cell death and proteolysis of inflammatory proteins. We found that the peptide aldehyde proteasome inhibitors, MG115 and MG132, block lysosome rupture, degradation of inflammatory proteins and necrotic cell death mediated by the lysosome-destabilizing peptide LLOMe. However, non-aldehyde proteasome inhibitors failed to prevent LLOMe-induced cell death suggesting that aldehyde proteasome inhibitors triggered a pleotropic effect. We have previously shown that cathepsin C controls lysosome rupture, necrotic cell death and the adaptive immune response mediated by LLOMe. Using recombinant cathepsin C, we found that aldehyde proteasome inhibitors directly block cathepsin C, which presumably prevents LLOMe toxicity. The cathepsin B inhibitor CA-074-Me also blocks lysosome rupture and necrotic cell death mediated by a wide range of necrosis inducers, including LLOMe. Using cathepsin-deficient cells and recombinant cathepsins, we demonstrate that the cathepsins B and C are not required for the CA-074-Me block of necrotic cell death. Taken together, our findings demonstrate that lysosome-destabilizing adjuvants trigger an early proteolytic cascade, involving cathepsin C and a CA-074-Me-dependent protease. Identification of these early events leading to lysosome rupture will be crucial in our understanding of processes controlling necrotic cell death and immune responses mediated by lysosome-destabilizing adjuvants.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2014 |
|---|---|
| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
PloS one - 9(2014), 6 vom: 25., Seite e95032 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Brojatsch, Jürgen [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 20.01.2015 Date Revised 21.10.2021 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.1371/journal.pone.0095032 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM238836592 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM238836592 | ||
| 003 | DE-627 | ||
| 005 | 20231224114642.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2014 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1371/journal.pone.0095032 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0796.xml |
| 035 | |a (DE-627)NLM238836592 | ||
| 035 | |a (NLM)24893007 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Brojatsch, Jürgen |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants |
| 264 | 1 | |c 2014 | |
| 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 20.01.2015 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Recent studies have linked necrotic cell death and proteolysis of inflammatory proteins to the adaptive immune response mediated by the lysosome-destabilizing adjuvants, alum and Leu-Leu-OMe (LLOMe). However, the mechanism by which lysosome-destabilizing agents trigger necrosis and proteolysis of inflammatory proteins is poorly understood. The proteasome is a cellular complex that has been shown to regulate both necrotic cell death and proteolysis of inflammatory proteins. We found that the peptide aldehyde proteasome inhibitors, MG115 and MG132, block lysosome rupture, degradation of inflammatory proteins and necrotic cell death mediated by the lysosome-destabilizing peptide LLOMe. However, non-aldehyde proteasome inhibitors failed to prevent LLOMe-induced cell death suggesting that aldehyde proteasome inhibitors triggered a pleotropic effect. We have previously shown that cathepsin C controls lysosome rupture, necrotic cell death and the adaptive immune response mediated by LLOMe. Using recombinant cathepsin C, we found that aldehyde proteasome inhibitors directly block cathepsin C, which presumably prevents LLOMe toxicity. The cathepsin B inhibitor CA-074-Me also blocks lysosome rupture and necrotic cell death mediated by a wide range of necrosis inducers, including LLOMe. Using cathepsin-deficient cells and recombinant cathepsins, we demonstrate that the cathepsins B and C are not required for the CA-074-Me block of necrotic cell death. Taken together, our findings demonstrate that lysosome-destabilizing adjuvants trigger an early proteolytic cascade, involving cathepsin C and a CA-074-Me-dependent protease. Identification of these early events leading to lysosome rupture will be crucial in our understanding of processes controlling necrotic cell death and immune responses mediated by lysosome-destabilizing adjuvants | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adjuvants, Pharmaceutic |2 NLM | |
| 650 | 7 | |a Aldehydes |2 NLM | |
| 650 | 7 | |a Antigens, Bacterial |2 NLM | |
| 650 | 7 | |a Bacterial Toxins |2 NLM | |
| 650 | 7 | |a Dipeptides |2 NLM | |
| 650 | 7 | |a Leupeptins |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a Proteasome Inhibitors |2 NLM | |
| 650 | 7 | |a anthrax toxin |2 NLM | |
| 650 | 7 | |a carbobenzoxy-leucyl-leucyl-norvalinal |2 NLM | |
| 650 | 7 | |a leucyl-leucine-methyl ester |2 NLM | |
| 650 | 7 | |a 13022-42-9 |2 NLM | |
| 650 | 7 | |a N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline |2 NLM | |
| 650 | 7 | |a 134448-10-5 |2 NLM | |
| 650 | 7 | |a Cathepsin C |2 NLM | |
| 650 | 7 | |a EC 3.4.14.1 |2 NLM | |
| 650 | 7 | |a Cathepsin B |2 NLM | |
| 650 | 7 | |a EC 3.4.22.1 |2 NLM | |
| 700 | 1 | |a Lima, Heriberto |e verfasserin |4 aut | |
| 700 | 1 | |a Kar, Alak K |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobson, Lee S |e verfasserin |4 aut | |
| 700 | 1 | |a Muehlbauer, Stefan M |e verfasserin |4 aut | |
| 700 | 1 | |a Chandran, Kartik |e verfasserin |4 aut | |
| 700 | 1 | |a Diaz-Griffero, Felipe |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t PloS one |d 2006 |g 9(2014), 6 vom: 25., Seite e95032 |w (DE-627)NLM167327399 |x 1932-6203 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2014 |g number:6 |g day:25 |g pages:e95032 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1371/journal.pone.0095032 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2014 |e 6 |b 25 |h e95032 | ||