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Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB
N Inohara1, T Koseki, L del Peso
1Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Abstract:
Ced-4 and Apaf-1 belong to a major class of apoptosis regulators that contain caspase-recruitment (CARD) and nucleotide-binding oligomerization domains. Nod1, a protein with an NH2-terminal CARD-linked to a nucleotide-binding domain and a COOH-terminal segment with multiple leucine-rich repeats, was identified. Nod-1 was found to bind to multiple caspases with long prodomains, but specifically activated caspase-9 and promoted caspase-9-induced apoptosis. As reported for Apaf-1, Nod1 required both the CARD and P-loop for function. Unlike Apaf-1, Nod1 induced activation of nuclear factor-kappa-B (NF-kappaB) and bound RICK, a CARD-containing kinase that also induces NF-kappaB activation. Nod1 mutants inhibited NF-kappaB activity induced by RICK, but not that resulting from tumor necrosis factor-alpha stimulation. Thus, Nod1 is a leucine-rich repeat-containing Apaf-1-like molecule that can regulate both apoptosis and NF-kappaB activation pathways.
Insights
Researchers identified Nod1, an Apaf-1-like molecule regulating apoptosis and NF-kappaB activation. Nod1 specifically activates caspase-9, promoting apoptosis and activating nuclear factor-kappa-B (NF-kappaB) via RICK.
Area of Science:
- Cellular Biology
- Immunology
Background:
- Ced-4 and Apaf-1 are key apoptosis regulators with caspase-recruitment (CARD) and nucleotide-binding oligomerization domains.
- Apoptosis and NF-kappaB pathways are critical cellular processes with distinct regulatory mechanisms.
Purpose of the Study:
- To identify and characterize novel regulators of apoptosis and NF-kappaB signaling.
- To elucidate the functional domains and interaction partners of the newly identified Nod1 protein.
Main Methods:
- Protein identification and domain analysis.
- Caspase activation assays and apoptosis induction studies.
- NF-kappaB activation assays and protein-protein interaction studies (e.g., RICK binding).
Main Results:
- Nod1, containing CARD and nucleotide-binding domains, was identified as an Apaf-1-like molecule.
- Nod1 specifically activated caspase-9, promoting apoptosis and requiring CARD and P-loop domains for function.
- Nod1 activated NF-kappaB, binding to RICK and modulating RICK-induced, but not TNF-alpha-induced, NF-kappaB activity.
Conclusions:
- Nod1 is a novel regulator linking apoptosis and NF-kappaB activation pathways.
- Nod1's dual role in apoptosis (via caspase-9) and NF-kappaB (via RICK) highlights its significance in immune and cellular responses.