Linear ubiquitination improves NFAT1 protein stability and facilitates NFAT1 signalling in Kawasaki disease

Abstract

NFAT1 is known for its roles in T cell development and activation. So far, the phosphorylation of NFAT1 has been extensively studied, but the other post‐translational modifications of NFAT1 remain largely unknown. In this study, we reported that NFAT1 is a linearly ubiquitinated substrate of linear ubiquitin chain assembly complex (LUBAC). LUBAC promoted NFAT1 linear ubiquitination, which in turn inhibited K48‐linked polyubiquitination of NFAT1 and therefore increased NFAT1 protein stability. Interestingly, the linear ubiquitination levels of NFAT1 in patients with the Kawasaki disease were upregulated. Further studies demonstrated that the patients with the Kawasaki disease had increased mRNA levels of HOIL‐1L. These findings revealed a linearly ubiquitinated substrate of LUBAC and an important biological function of NFAT1 linear ubiquitination in the Kawasaki disease and therefore may provide a novel strategy for the treatment of the Kawasaki disease.

Role of developmental pathways in disease

“…Finally, we recommend looking into a recently published research article by Ying Miao et al . [19] that revealed a biological function for linear ubiquitination of NFAT1, a factor involved in developmental pathways, in Kawasaki disease.…”

“…We also invite our readers to read The FEBS Journal articles published in the last couple of years that are linked to the theme of developmental pathways in disease (and which are not included in this Collection); these involve, among others, an overview of the role of Notch signaling in development and disease [16], a summary of the impact of serine pseudoproteases on physiology and pathology [17], and also a review of the developmental processes involved in wound repair [18]. Finally, we recommend looking into a recently published research article by Ying Miao et al [19] that revealed a biological function for linear ubiquitination of NFAT1, a factor involved in developmental pathways, in Kawasaki disease.…”

Novel role for linear ubiquitination in regulating NFAT1 stability

“…However, a cycloheximide chase experiment revealed enhanced NFAT1 degradation in the absence of HOIP, which can be prevented by proteasome inhibitors [7]. Miao et al [7] next demonstrate that LUBAC-mediated linear ubiquitination prevents degradative K48-linked ubiquitination of NFAT1, promoting nuclear translocation of NFAT1 and subsequent increase in target gene expression (Fig. 1).…”

“…Interestingly, the authors noticed that overexpression of LUBAC components increases co-expression of NFAT1, while knock-down of HOIP has an opposite effect, which could not be linked to the changes in the Nfatc2 (NFAT1) mRNA levels. However, a cycloheximide chase experiment revealed enhanced NFAT1 degradation in the absence of HOIP, which can be prevented by proteasome inhibitors [7]. Miao et al [7] next demonstrate that LUBAC-mediated linear ubiquitination prevents degradative K48-linked ubiquitination of NFAT1, promoting nuclear translocation of NFAT1 and subsequent increase in target gene expression (Fig.…”

“…Despite the advancements made in recent decades, the precise mechanisms that regulate NFAT1 activation (aside from the calcineurin-mediated dephosphorylation) largely remain unknown. In the current issue of The FEBS Journal, Miao et al [7] investigated the role of linear ubiquitination in the regulation of NFAT1 signalling.…”