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Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1?.

ABSTRACT: Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of proinflammatory cytokines, via a mechanism that remains undefined. Here we show that IL-1? is a substrate for granzyme B and that proteolysis potently enhanced the biological activity of this cytokine in vitro as well as in vivo. Consistent with this, compared with full-length IL-1?, granzyme B-processed IL-1? exhibited more potent activity as an immunoadjuvant in vivo. Furthermore, proteolysis of IL-1? within the same region, by proteases such as calpain and elastase, was also found to enhance its biological potency. Thus, IL-1? processing by multiple immune-related proteases, including granzyme B, acts as a switch to enhance the proinflammatory properties of this cytokine.

SUBMITTER: Afonina IS

PROVIDER: S-EPMC3319689 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α.

Afonina Inna S IS Tynan Graham A GA Logue Susan E SE Cullen Sean P SP Bots Michael M Lüthi Alexander U AU Reeves Emer P EP McElvaney Noel G NG Medema Jan P JP Lavelle Ed C EC Martin Seamus J SJ

Molecular cell 20111001 2

Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of proinflammatory cytokines, via a mechanism that remains undefined. Here we show that IL-1α is a substrate for granzyme B and that proteolysis potently enhanced the biological activity of this ...[more]

PMID: 22017873

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Project description:BackgroundThe HIV1 protein Vpr assembles with and acts through an ubiquitin ligase complex that includes DDB1 and cullin 4 (CRL4) to cause G2 cell cycle arrest and to promote degradation of both uracil DNA glycosylase 2 (UNG2) and single-strand selective mono-functional uracil DNA glycosylase 1 (SMUG1). DCAF1, an adaptor protein, is required for Vpr-mediated G2 arrest through the ubiquitin ligase complex. In work described here, we used UNG2 as a model substrate to study how Vpr acts through the ubiquitin ligase complex. We examined whether DCAF1 is essential for Vpr-mediated degradation of UNG2 and SMUG1. We further investigated whether Vpr is required for recruiting substrates to the ubiquitin ligase or acts to enhance its function and whether this parallels Vpr-mediated G2 arrest.Methodology/principal findingsWe found that DCAF1 plays an important role in Vpr-independent UNG2 and SMUG1 depletion. UNG2 assembled with the ubiquitin ligase complex in the absence of Vpr, but Vpr enhanced this interaction. Further, Vpr-mediated enhancement of UNG2 degradation correlated with low Vpr expression levels. Vpr concentrations exceeding a threshold blocked UNG2 depletion and enhanced its accumulation in the cell nucleus. A similar dose-dependent trend was seen for Vpr-mediated cell cycle arrest.Conclusions/significanceThis work identifies UNG2 and SMUG1 as novel targets for CRL4(DCAF1)-mediated degradation. It further shows that Vpr enhances rather than enables the interaction between UNG2 and the ubiquitin ligase. Vpr augments CRL4(DCAF1)-mediated UNG2 degradation at low concentrations but antagonizes it at high concentrations, allowing nuclear accumulation of UNG2. Further, the protein that is targeted to cause G2 arrest behaves much like UNG2. Our findings provide the basis for determining whether the CRL4(DCAF1) complex is alone responsible for cell cycle-dependent UNG2 turnover and will also aid in establishing conditions necessary for the identification of additional targets of Vpr-enhanced degradation.

Dataset Information

Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1?.

Publications

Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1α.

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