COP9 Signalosome Interaction with UspA/Usp15 Deubiquitinase Controls VeA-Mediated Fungal Multicellular Development

Abstract

COP9 signalosome (CSN) and Den1/A deneddylases physically interact and promote multicellular development in fungi. CSN recognizes Skp1/cullin-1/Fbx E3 cullin-RING ligases (CRLs) without substrate and removes their posttranslational Nedd8 modification from the cullin scaffold. This results in CRL complex disassembly and allows Skp1 adaptor/Fbx receptor exchange for altered substrate specificity. We characterized the novel ubiquitin-specific protease UspA of the mold Aspergillus nidulans, which corresponds to CSN-associated human Usp15 and interacts with six CSN subunits. UspA reduces amounts of ubiquitinated proteins during fungal development, and the uspA gene expression is repressed by an intact CSN. UspA is localized in proximity to nuclei and recruits proteins related to nuclear transport and transcriptional processing, suggesting functions in nuclear entry control. UspA accelerates the formation of asexual conidiospores, sexual development, and supports the repression of secondary metabolite clusters as the derivative of benzaldehyde (dba) genes. UspA reduces protein levels of the fungal NF-kappa B-like velvet domain protein VeA, which coordinates differentiation and secondary metabolism. VeA stability depends on the Fbx23 receptor, which is required for light controlled development. Our data suggest that the interplay between CSN deneddylase, UspA deubiquitinase, and SCF-Fbx23 ensures accurate levels of VeA to support fungal development and an appropriate secondary metabolism.

COP9 signalosome: Discovery, conservation, activity, and function

“…It is worth exploring the differences of CSN's biochemical functions in single‐cellular organisms (e.g., yeast) and multicellular organisms (Goubeaud et al 1996; Meister et al 2019). Also, it is of interest to study the contribution of CSN to plants’ colonization onto land in basal land plant species.…”

The COP9 Signalosome: A Multi-DUB Complex

“…In absence of CSN5, Ubp12p is entirely lost from the CSN [ 14 ]. In A. nidulans , UspA presumably interacts with the helical bundle of the CSN (see Figure 1 ) [ 15 ]. In human cells, the association between the CSN and USP15 was demonstrated by diverse methods [ 61 ].…”

“…The CSN recruits USP15 to protect components of CRLs during the remodeling process of the E3 ligase complexes [ 47 , 61 ]. Recently, UspA-dependent protection of the F-box protein F-box23 was shown in A. nidulans [ 15 ]. Interestingly, F-box23 is presumably the paralog of β-TrCP in mammalian cells, the SR of CRL1 β-TrCP responsible for the ubiquitylation of IκBα [ 71 ].…”

“…Interestingly, F-box23 is presumably the paralog of β-TrCP in mammalian cells, the SR of CRL1 β-TrCP responsible for the ubiquitylation of IκBα [ 71 ]. By stabilizing the F-box23, the CSN-associated UspA reduces protein levels of the fungal NF-κB-like velvet domain protein VeA, which coordinates differentiation and secondary metabolism [ 15 ]. Further, USP15 deubiquitylates IκBα enhancing its stability.…”

“…CSN5 is involved in CSN-USP15/Ubp12 interaction [ 14 ]. In addition, in A. nidulans USP15/UspA is presumably associated with the entire helical bundle [ 15 ]. So far, there is no crystal or cryo-structure of USP48 available.…”