caspase-1

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TRICHOTHECENE MYCOTOXINS ACTIVATE INFLAMMATORY RESPONCE IN HUMAN

MACROPHAGES/CASPASE 1

http://www.jimmunol.org/cgi/content/abstract/182/10/6418

ACTIVE CASPASE-1 IS A REGULATOR OF UNCONVENTIONAL PROTEIN SECRETION.

Caspase-1 has a well-established function in inflammation via

the activation of proinflammatory cytokines (Dinarello, 1998). In

addition, it has been reported to mediate either cell death (Cookson

and Brennan, 2001) or survival (Gurcel et al., 2006) upon infection

by certain pathogens. Here we found that activation of

caspase-1 by inflammasome complexes is directly linked to unconventional

secretion of a variety of leaderless proteins, most

likely via a direct or indirect physical interaction.

Unconventional secretion has been a mystery since its discovery

but can be clearly distinguished from the classical secretion

pathway.

http://www.sciencedirect.com/science?_ob=MImg & _imagekey=B6WSN-4S0GXH1-J-3 & _cdi=7\

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cle.pdf

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INSTITUTE OF CELL BIOLOGY/RESEARCH

http://www.cell.biol.ethz.ch/research/beer/research

2006 Nov;13(11):1938-49. Epub 2006 Mar 31.

The estrogen-responsive B box protein: a novel enhancer of interleukin-1beta

secretion.

Munding C, Keller M, Niklaus G, Papin S, Tschopp J, Werner S, Beer HD.

Department of Biology, Institute of Cell Biology, ETH Zurich, ETH Honggerberg,

CH-8093 Zurich, Switzerland.

The estrogen-responsive B box protein (EBBP) and Pyrin belong to a family of

structurally related proteins. While mutations in the pyrin gene cause an

autoinflammatory disease, the biological function of EBBP is unknown. In this

study, we identified the proinflammatory cytokine interleukin-1beta (IL-1beta)

as an EBBP-binding partner. Furthermore, caspase-1 and NACHT, LRR and Pyrin

domain containing protein (NALP) 1, two components of the recently identified

inflammasome, a platform for the activation of caspase-1, also interact with

EBBP. These proteins bind to the RFP domain of EBBP, suggesting that this domain

of so far unknown function is an important protein-binding domain. EBBP was

secreted in a caspase-1-dependent manner from cultured cells, and its secretion

was enhanced by IL-1beta. Vice versa, endogenous and overerexpressed EBBP

increased IL-1beta secretion. These results provide evidence for a role of EBBP

in innate immunity by enhancing the alternative secretion pathway of IL-1beta.

2009 Mar;10(3):241-7.

The inflammasome: a caspase-1-activation platform that regulates immune

responses and disease pathogenesis.

Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G.

Department of Pathology, Comprehensive Cancer Center, The University of Michigan

Medical School, Ann Arbor, Michigan 48109, USA.

The inflammasome is a multiprotein complex that mediates the activation of

caspase-1, which promotes secretion of the proinflammatory cytokines interleukin

1beta (IL-1beta) and IL-18, as well as 'pyroptosis', a form of cell death

induced by bacterial pathogens. Members of the Nod-like receptor family,

including NLRP1, NLRP3 and NLRC4, and the adaptor ASC are critical components of

the inflammasome that link microbial and endogenous 'danger' signals to

caspase-1 activation. Several diseases are associated with dysregulated

activation of caspase-1 and secretion of IL-1beta. Thus, understanding

inflammasome pathways may provide insight into disease pathogenesis that might

identify potential targets for therapeutic intervention.

2009 Feb;21(1):10-6. Epub 2009 Feb 14.

Sensing pathogens and danger signals by the inflammasome.

Pedra JH, Cassel SL, Sutterwala FS.

Institute for Integrative Genome Biology and Department of Entomology,

University of California-Riverside, 92521, USA. joao.pedra@...

Comment in:

Curr Opin Immunol. 2009 Feb;21(1):1-2.

The NLR (nucleotide-binding domain leucine-rich repeat containing) family of

intracellular sensors is a crucial component of the innate immune system. A

number of NLR family members can form multiprotein complexes, called

inflammasomes, and are capable of activating the cysteine protease caspase-1 in

response to a wide range of stimuli including both microbial and self-molecules.

Caspase-1 activation leads to processing and secretion of the proinflammatory

cytokines interleukin-1beta (IL-1beta) and IL-18, which play crucial roles in

host defense to infectious insults. Dysregulation of the inflammasome has also

been linked to a number of autoinflammatory and autoimmune disorders. Recent

advances in the inflammasome field will be discussed in this review.

EBBP

http://mend.endojournals.org/cgi/content/abstract/12/11/1733