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A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants.

ABSTRACT: 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.

SUBMITTER: Brojatsch J

PROVIDER: S-EPMC4043491 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants.

Brojatsch Jürgen J Lima Heriberto H Kar Alak K AK Jacobson Lee S LS Muehlbauer Stefan M SM Chandran Kartik K Diaz-Griffero Felipe F

PloS one 20140603 6

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 pept ...[more]

PMID: 24893007

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Project description:As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as "lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol." Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome-associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death.The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage.

Project description:How interactions among multiple predators affect the stability of trophic cascades is a topic of special ecological interest. To examine factors affecting the stability of the classic tri-trophic oyster reef cascade within a different context, configurations of three predators, including the Gulf toadfish, Gulf stone crab, and oystershell mud crab, were manipulated together with either oyster shell or limestone gravel substrate within a multiple predator effects (MPE) experiment. Additionally, a complimentary set of trait-mediated-indirect interaction (TMII) experiments examined the inhibition of oyster consumption relative to mud-crab size and top predator identity in the absence of other cues and factors. The classic tri-trophic cascade formed by the toadfish-mud crab-oyster configuration was potentially weakened by several interactions within the MPE experiment. Consumption of oysters and mud crabs by the intraguild stone crab was undeterred by the presence of toadfish. Although mud crab feeding was inhibited in the presence of both toadfish and stone crabs, estimated non-consumptive effects (NCEs) were weaker for stone crabs in the MPE experiment. Consequently, the total effect was destabilizing when all three predator species were together. Inhibition of mud crab feeding was inversely related to direct predation on mud crabs within the MPE experiment. Complimentary TMII experiments revealed greater inhibition of mud crab feeding in response to stone crabs under sparse conditions. TMII experiments also implied that inhibition of mud crab feeding could have largely accounted for NCEs relative to oysters within the MPE experiment, as opposed to interference by other mud crabs or top predators. An inverse relationship between mud crab size and NCE strength in the TMII experiment disclosed another potentially destabilizing influence on the tri-trophic-cascade. Finally, although habitat complexity generally dampened the consumption of oysters across MPE treatments, complex habitat promoted mud crab feeding in the presence of toadfish alone. This study underscores how ecological interactions can mediate trophic cascades and provides some additional insights into the trophic dynamics of oyster reefs for further testing under natural conditions.

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A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants.

Publications

A proteolytic cascade controls lysosome rupture and necrotic cell death mediated by lysosome-destabilizing adjuvants.

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