Regulatory mechanisms and therapeutic potential of JAB1 in neurological development and disorders

Abstract

c-Jun activation domain binding protein-1 (JAB1) is a multifunctional regulator that plays vital roles in diverse cellular processes. It regulates AP-1 transcriptional activity and also acts as the fifth component of the COP9 signalosome complex. While JAB1 is considered an oncoprotein that triggers tumor development, recent studies have shown that it also functions in neurological development and disorders. In this review, we summarize the general features of the JAB1 gene and protein, and present recent updates on the regulation of JAB1 expression. Moreover, we also highlight the functional roles and regulatory mechanisms of JAB1 in neurodevelopmental processes such as neuronal differentiation, synaptic morphogenesis, myelination, and hair cell development and in the pathogenesis of some neurological disorders such as Alzheimer's disease, multiple sclerosis, neuropathic pain, and peripheral nerve injury. Furthermore, current challenges and prospects are discussed, including updates on drug development targeting JAB1.

Keywords: COP9 signalosome; Neurodevelopment; Neurological disorders; Regulatory mechanisms; c-Jun activation domain binding protein-1.

Fig. 1

The profile of JAB1 protein. A The bootstrap consensus phylogenetic tree of JAB1 proteins from different species. The phylogenetic tree was constructed by using MEGA software version 11.0.13. B Human JAB1 amino acid sequences. MPN, NES, and C-terminal domains are shown in yellow, red, and cyan, respectively. JAMM motif is marked by a black box. C The structure of human JAB1 is shown based on the data from Protein Data Bank (ID 4D18; https://www.rcsb.org/structure/4D18). MPN, NES, and C-terminal domains are shown in yellow, red, and cyan, respectively. JAMM motif is exhibited by ball and sticks

Fig. 2

A summary scheme of molecular pathways involved in JAB1 expression. The sequence in the dotted box indicates the promoter of the JAB1 gene. The identified transcription factor binding sites are color-coded. The transcription start site is marked as “+1”. “P” and “Ub” represent the phosphorylation and ubiquitination of target proteins, respectively

Fig. 3

Schematic overview of JAB1 in neurodevelopment and neurological diseases. The downstream factors and potential mechanisms of JAB1 in different processes are depicted