The mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) paracaspase, a key component of the Carma1/Bcl10/ MALT1 signalosome, is critical for NF-κB signaling in multiple contexts. MALT1 is thought to function as a scaffold and protease to promote signaling; however, the biochemical and structural basis of paracaspase action remains largely unknown. Here we report the 1.75-Å resolution crystal structure of the MALT1 paracaspase region, which contains the paracaspase domain and an ensuing Ig-like domain. The paracaspase and the Ig domains appear as a single folding unit and interact with each other through extensive van der Waals contacts and hydrogen bonds. The paracaspase domain adopts a fold that is nearly identical to that of classic caspases and homodimerizes similarly to form an active protease. Unlike caspases, the active and mature form of the paracaspase domain remains a single uncleaved polypeptide and specifically recognizes the bound peptide inhibitor Val-Arg-Pro-Arg. In particular, the carboxyl-terminal amino acid Arg of the inhibitor is coordinated by three highly conserved acidic residues. This structure serves as an important framework for deciphering the function and mechanism of paracaspases exemplified by MALT1.T he transcription factor NF-κB is a key constituent of all cell types and is activated by various receptors to regulate survival, proliferation, migration, and differentiation (1). In particular, NF-κB functions early in the development and maintenance of innate and adaptive immune systems and execution of the immune response. Although caspases, cysteine proteases that cleave substrate proteins after aspartate residues, are widely known as executioners of programmed cell death or apoptosis (2), a subset and related members also activate NF-κB to promote lymphocyte proliferation and inflammation. One such caspase-like family member, the mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) paracaspase, was identified through weak sequence homology to caspases (3) and was subsequently found to play an important role in lymphocyte activation (4) and disease progression in MALT lymphomas (5).Upon antigen receptor stimulation, the MALT1 paracaspase and Bcl10 assemble into the Carma1/Bcl10/MALT1 (CBM) signalosome to activate NF-κB in the adaptive immune system. Specifically during T-cell receptor signaling, the CBM signalosome is thought to oligomerize MALT1 and its associated ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6) or TRAF2 (6, 7), which in turn facilitates K63-linked polyubiquitylation of multiple proteins including the regulatory γ-subunit of the IκB kinase (IKK) complex (6, 7), TRAF6 itself (7), Bcl10 (8), and MALT1 (9). Poly ubiquitylation of these proteins ultimately leads to the recruitment of transforming growth factor β-activated kinase 1 (TAK1), TAK1 binding protein (TAB), and the IKK complex to lipid rafts where the IKKβ-subunit is phosphorylated and activated. In the canonical NF-κB pathway, the activated IKK complex ph...
The N-acetyltransferase arrest defective 1 (ARD1) is an important regulator of cell growth and differentiation that has emerged recently as a critical molecule in cancer progression. However, the regulation of the enzymatic and biological activities of human ARD1 (hARD1) in cancer is presently poorly understood. Here, we report that hARD1 undergoes autoacetylation and that this modification is essential for its functional activation. Using liquid chromatography-tandem mass spectrometry and site-directed mutational analyses, we identified K136 residue as an autoacetylation target site. K136R mutation abolished the ability of hARD1 to promote cancer cell growth in vitro and tumor xenograft growth in vivo. Mechanistic investigations revealed that hARD1 autoacetylation stimulated cyclin D1 expression through activation of the transcription factors β-catenin and activator protein-1. Our results show that hARD1 autoacetylation is critical for its activation and its ability to stimulate cancer cell proliferation and tumorigenesis. Cancer Res; 70(11); 4422-32. ©2010 AACR.
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