Fig. 4: Role of WWP1 in various pathological conditions.
From: WWP1 E3 ligase at the crossroads of health and disease
A WWP1 plays crucial role in several viral diseases, where it helps in viral budding by interacting with host machineries. For instance, WWP1 interacts with and facilitates polyubiquitination of Ebola virus VP40 (eVP40) matrix proteins. Then, it interacts with and recruits endosomal sorting complexes required for transport III (ESCRT-III) complex to the neck of the viral vesicles, ultimately leading to the release/budding of the EBOLA virus particles. B WWP1 interacts with spastic paraplegia 20 (SPG20)/Spartin to promote its monoubiquitination, subcellular localization, and protein levels, thereby regulating the proper number and size of lipid droplets and ultimately maintaining proper neuronal health. Deregulation of WWP1 alters this pathway, leading to neurological diseases like Troyer syndrome. C WWP1 mutation (arginine to glutamine at 441, R441Q) impairs WWP1-mediated ubiquitination of αENaC (amiloride-sensitive epithelial sodium channel), leading to hypernatremia and chicken muscular dystrophy. D WWP1 regulates aging in C. elegans via two reported mechanisms. First, WWP1 directly interacts with and facilitates multiple monoubiquitination of KLF-1 (kruppel-like factor-1), an essential and specific regulator of dietary restriction (DR)-induced longevity in C. elegans. Second, WWP1 gets phosphorylated by the DAF-2 insulin/IGF-1 signaling pathway (crucial for aging in C. elegans) and therefore might be instrumental for aging. E WWP1 promotes osteogenic diseases such as osteoporosis via ubiquitination and degradation of RUNX2 and JUNB (crucial transcription factors for osteogenic differentiation), which is antagonized by miR-142-5p. F WWP1 promotes cardiac disorders such as left ventricular hypertrophy and lethal ventricular arrhythmias by ubiquitination-mediated degradation of Connexin 43 (Cx43). WWP1 also promotes pressure overload-induced cardiac hypertrophy via promoting K27-mediated polyubiquitination of disheveled segment polarity protein 2 (DVL2) and thereby enhancing the DVL2/CaMKII/HDAC4/MEF2C signaling pathway.
