LaeA Control of Velvet Family Regulatory Proteins for Light-Dependent Development and Fungal Cell-Type Specificity

Sarikaya Bayram, Ö,zlem,Bayram, Ö,zgü,r,Valerius, Oliver,Park, Hee Soo,Irniger, Stefan,Gerke, Jennifer,Ni, Min,Han, Kap-Hoon,Yu, Jae-Hyuk,Braus, Gerhard H. Public Library of Science 2010 PLoS genetics Vol.6 No.12

<▼1><P>VeA is the founding member of the velvet superfamily of fungal regulatory proteins. This protein is involved in light response and coordinates sexual reproduction and secondary metabolism in <I>Aspergillus nidulans</I>. In the dark, VeA bridges VelB and LaeA to form the VelB-VeA-LaeA (velvet) complex. The VeA-like protein VelB is another developmental regulator, and LaeA has been known as global regulator of secondary metabolism. In this study, we show that VelB forms a second light-regulated developmental complex together with VosA, another member of the velvet family, which represses asexual development. LaeA plays a key role, not only in secondary metabolism, but also in directing formation of the VelB-VosA and VelB-VeA-LaeA complexes. LaeA controls VeA modification and protein levels and possesses additional developmental functions. The <I>laeA</I> null mutant results in constitutive sexual differentiation, indicating that LaeA plays a pivotal role in inhibiting sexual development in response to light. Moreover, the absence of LaeA results in the formation of significantly smaller fruiting bodies. This is due to the lack of a specific globose cell type (Hülle cells), which nurse the young fruiting body during development. This suggests that LaeA controls Hülle cells. In summary, LaeA plays a dynamic role in fungal morphological and chemical development, and it controls expression, interactions, and modification of the velvet regulators.</P></▼1><▼2><P><B>Author Summary</B></P><P>Numerous fungi have the potential to infect immunocompromised patients or to contaminate and spoil our nutrients. They represent an increasing danger that threatens public health and agriculture. This requires improved understanding of fungal growth, development, dissemination of spores, and mycotoxin production. We have discovered two related fungal specific protein complexes that provide a molecular link among spore formation, fungal development, and secondary metabolite production. The subunit allocation of both complexes depends on each other, and they share a common subunit. These complexes comprise three related and in fungi conserved proteins of the velvet family that function in concert with a known regulator of secondary metabolism, LaeA. This protein controls the formation of both complexes but is only a part of the trimeric complex. We found that this regulator of secondary metabolism also possesses several developmental control functions in gene expression. These protein complexes discovered in the fungal model system <I>Aspergillus nidulans</I> are conserved in fungal pathogens where they might provide novel insights for understanding growth, development, and interaction with their respective hosts.</P></▼2>

An alternative IIB embedding of F(4) gauged supergravity

Jeong, Jaehoon,Kelekci, Ö,zgü,r,Colgá,in, Eoin Ó Springer-Verlag 2013 Journal of high energy physics Vol.2013 No.5

The Velvet Family of Fungal Regulators Contains a DNA-Binding Domain Structurally Similar to NF-κB

Ahmed, Yasar Luqman,Gerke, Jennifer,Park, Hee-Soo,Bayram, Ö,zgü,r,Neumann, Piotr,Ni, Min,Dickmanns, Achim,Kim, Sun Chang,Yu, Jae-Hyuk,Braus, Gerhard H.,Ficner, Ralf Public Library of Science 2013 PLoS biology Vol.11 No.12

<P>Morphological development of fungi and their combined production of secondary metabolites are both acting in defence and protection. These processes are mainly coordinated by <I>velvet</I> regulators, which contain a yet functionally and structurally uncharacterized <I>velvet</I> domain. Here we demonstrate that the <I>velvet</I> domain of VosA is a novel DNA-binding motif that specifically recognizes an 11-nucleotide consensus sequence consisting of two motifs in the promoters of key developmental regulatory genes. The crystal structure analysis of the VosA <I>velvet</I> domain revealed an unforeseen structural similarity with the Rel homology domain (RHD) of the mammalian transcription factor NF-κB. Based on this structural similarity several conserved amino acid residues present in all <I>velvet</I> domains have been identified and shown to be essential for the DNA binding ability of VosA. The <I>velvet</I> domain is also involved in dimer formation as seen in the solved crystal structures of the VosA homodimer and the VosA-VelB heterodimer. These findings suggest that defence mechanisms of both fungi and animals might be governed by structurally related DNA-binding transcription factors.</P><P><B>Author Summary</B></P><P>In many fungi, developmental processes and the synthesis of nonessential chemicals (secondary metabolites) are regulated by various external stimuli, such as light. Although fungi employ them for defensive purposes, secondary metabolites range from useful antibiotics to powerful toxins, so understanding the molecular processes that regulate their synthesis is of particular interest to us. In the mold <I>Aspergillus nidulans</I> the main regulators of these processes are the so-called “<I>velvet</I>” proteins VeA, VelB, and VosA, which share a 150-amino acid region known as the <I>velvet</I> domain. <I>Velvet</I> proteins interact with each other, alone (“homodimers”), in various combinations (“heterodimers”), and also with other proteins, but the molecular mechanism by which these proteins exert their regulatory function has been unclear. In this work we show that <I>velvet</I> proteins form a family of fungus-specific transcription factors that directly bind to target DNA, even though analysis of their amino acid sequence does not reveal any known DNA-binding domains or motifs. We determined the three-dimensional structure of the VosA-VosA homodimer and the VosA-VelB heterodimer and found that the structure of the <I>velvet</I> domain is strongly reminiscent of the N-terminal immunoglobulin-like domain found in the mammalian transcription factor NFκB-p50, despite the very low sequence similarity. We propose that, like NFκB, various homo- or heterodimers of <I>velvet</I> proteins modulate gene expression to drive development and defensive pathways in fungi.</P>

SMAD4 Suppresses AURKA-Induced Metastatic Phenotypes via Degradation of AURKA in a TGFβ-Independent Manner

Jia, Lina,Lee, Hun Seok,Wu, Chun Fu,Kundu, Juthika,Park, Sang Gyu,Kim, Ryong Nam,Wang, Li-Hui,Erkin, Ö,zgü,r Cem,Choi, Jong-Sun,Chae, Seoung Wan,Yang, Ho Bin,Choi, Yoon-La,Shin, Young Kee American Association for Cancer Research 2014 Molecular Cancer Research Vol.12 No.12

<P>SMAD4 has been suggested to inhibit the activity of the WNT/β-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/β-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of β-catenin/T-cell factor (TCF) complex by stabilizing β-catenin through the inhibition of GSK-3β. Here, SMAD4 modulated AURKA in a TGFβ-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the β-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of β-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and β-catenin was independent of TGFβ signaling because blockage of TGFβR1 or restoration of TGFβ signaling did not prevent suppression of AURKA and β-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of β-catenin transcriptional activity via AURKA degradation in a TGFβ-independent manner.</P><P><B>Implications:</B> SMAD4 interacts with AURKA and antagonizes its tumor-promoting potential, thus demonstrating a novel mechanism of tumor suppression. <I>Mol Cancer Res; 12(12); 1779–95. ©2014 AACR</I>.</P>