Corrigendum to: Activation of caspases triggered by cytochrome c in vitro (FEBS 20097)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/117119/1/feb2s0014579398004657.pd

Caspase regulation in inflammation.

Caspases, or cysteine-dependent aspartate specific proteases, comprise a family of cysteine proteases that cleave after an aspartic acid residue. They have been implicated in two aspects of cellular signaling: proteolytic activation of specific interleukins and programmed cell death. Caspases are produced as single chain zymogens that possess a low protease activity. Caspase zymogens normally lie dormant in healthy cells and consist of a variable length caspase activation domain (CARD) followed by two subunits that comprise the catalytic domain. When a cell receives either a death stimulus or a signal to generate IL-1beta, a caspase cascade is initiated. To initiate this cascade, the stimulus must cause oligomerization of an adaptor molecule that in turn recruits multiple initiator caspase zymogens into close proximity with one another causing autocatalyic processing and subsequent activation. The only exception is caspase-9, a proapoptotic initiator caspase activated without autocatalytic processing. Activation of the initiator caspase is a critical step in determining cell fate and, as such, it is important to understand how it occurs and how it is regulated. Caspase-1 is the protease responsible for the proteolytic conversion of the inactive IL-1beta cytokine to its mature proinflammatory cytokine. IL-1beta is perhaps the most potent of endogenous pyrogens. We show that caspase-1 is activated via recruitment to its upstream adaptor Nod2 in response to an inflammatory stimulus. Furthermore, we demonstrate how Nod2 mutations found in Crohn's disease, a member of the inflammatory bowel disorders, lead to increased IL-1beta release, diagnostic for this disease. Endogenous inhibition of IL-1beta release is accomplished by ICEBERG, a novel CARD only decoy adaptor that binds caspase-1 and inhibits its activation and the consequent release of IL-1beta. While studying the homotypic interaction motifs that form the molecular glue that bind the signaling machinery responsible for caspase activation, we discovered a novel interaction motif called the pyrin domain (PYD). PYD is structurally related to the CARD, the death domain (DD), and the death effector domain (DED), all members of the 'death domain fold' superfamily. The DD, DED, CARD and PYD modules are found almost exclusively in proteins involved in apoptosis or inflammation.Ph.D.Biological SciencesHealth and Environmental SciencesImmunologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124077/2/3121946.pd

Activation of caspases triggered by cytochrome c in vitro1

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116354/1/feb2s0014579398003305.pd

ICEBERG A Novel Inhibitor of Interleukin-1β Generation

AbstractProIL-1β is a proinflammatory cytokine that is proteolytically processed to its active form by caspase-1. Upon receipt of a proinflammatory stimulus, an upstream adaptor, RIP2, binds and oligomerizes caspase-1 zymogen, promoting its autoactivation. ICEBERG is a novel protein that inhibits generation of IL-1β by interacting with caspase-1 and preventing its association with RIP2. ICEBERG is induced by proinflammatory stimuli, suggesting that it may be part of a negative feedback loop. Consistent with this, enforced retroviral expression of ICEBERG inhibits lipopolysaccharide-induced IL-1β generation. The structure of ICEBERG reveals it to be a member of the death-domain-fold superfamily. The distribution of surface charge is complementary to the homologous prodomain of caspase-1, suggesting that charge–charge interactions mediate binding of ICEBERG to the prodomain of caspase-1

Gli protein activity is controlled by multisite phosphorylation in vertebrate hedgehog signaling

Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity

Gli Protein Activity Is Controlled by Multisite Phosphorylation in Vertebrate Hedgehog Signaling

Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity

Gli protein activity is controlled by multisite phosphorylation in vertebrate Hedgehog signaling.

Gli proteins are transcriptional effectors of the Hedgehog (Hh) pathway in both normal development and cancer. We describe a program of multisite phosphorylation that regulates the conversion of Gli proteins into transcriptional activators. In the absence of Hh ligands, Gli activity is restrained by the direct phosphorylation of six conserved serine residues by protein kinase A (PKA), a master negative regulator of the Hh pathway. Activation of signaling leads to a global remodeling of the Gli phosphorylation landscape: the PKA target sites become dephosphorylated, while a second cluster of sites undergoes phosphorylation. The pattern of Gli phosphorylation can regulate Gli transcriptional activity in a graded fashion, suggesting a phosphorylation-based mechanism for how a gradient of Hh signaling in a morphogenetic field can be converted into a gradient of transcriptional activity

Caspase-12: an overview

SCOPUS: re.jinfo:eu-repo/semantics/publishe