Hearing Loss Caused by HCMV Infection through Regulating the Wnt and Notch Signaling Pathways

Abstract

Hearing loss is one of the most prevalent sensory disabilities worldwide with huge social and economic burdens. The leading cause of sensorineural hearing loss (SNHL) in children is congenital cytomegalovirus (CMV) infection. Though the implementation of universal screening and early intervention such as antiviral or anti-inflammatory ameliorate the severity of CMV-associated diseases, direct and targeted therapeutics is still seriously lacking. The major hurdle for it is that the mechanism of CMV induced SNHL has not yet been well understood. In this review, we focus on the impact of CMV infection on the key players in inner ear development including the Wnt and Notch signaling pathways. Investigations on these interactions may gain new insights into viral pathogenesis and reveal novel targets for therapy.

Keywords: Notch signaling pathway; Wnt signaling pathway; congenital cytomegalovirus infection; cytomegalovirus; inner ear development; sensorineural hearing loss.

Figure 1

Anatomy of the inner ear and the organ of Corti. The inner ear is divided into three sections: the semicircular canals, the vestibular and the cochlear. The organ of Corti is located inside the cochlear duct, responsible for transducing sound vibrations into nerve impulses. The organ of Corti consists of three rows of outer hair cells (OHCs) and one row of inner hair cells (IHCs) interspaced by supporting cells (SCs).

Figure 2

HCMV regulates the canonical Wnt/β-catenin signaling pathway. When Wnt pathway is off (Wnt receptor complex is not bound by a ligand), β-catenin is degraded through proteasome by the β-catenin destruction complex; the transcription of Wnt target genes is inhibited in the nucleus. When Wnt signal pathway is on and activated by binding Wnt ligand with the Frizzled receptor, the receptor recruits Dvl as a docking platform for components of β-catenin destruction complex, which promotes LRP5/6 phosphorylation and frees β-catenin. The freed β-catenin translocates to the nucleus where it interacts with TCF/LEF transcription factor to drive downstream target gene expression. HCMV regulates Wnt signaling pathway by the following routes: (1) HCMV US28 inhibits GSK3 activity via ROCK pathway and induces β-catenin translocation into the nucleus for Wnt target gene expression. (2) HCMV decreases poly-ADP-ribosylation activity of Tankyrase which stabilizes Axin and suppresses Wnt pathway. (3) HCMV induces β-catenin degradation and attenuates Wnt target gene expression.

Figure 3

HCMV dysregulates the Notch signaling pathway. When Notch ligands (Dll1/3/4 and Jag1/2) bind with Notch receptors, proteolytic cleavage of Notch receptors by ADAM and γ-secretase complex releases Notch intracellular domain (NICD). Then NICD translocates into nucleus and binds with CSL (CBF1/SuH/Lag-1) to activate transcription of target effector genes (Hes and Hey). Hes1 and Hes5 can facilitate STAT3 phosphorylation which leads to STAT3 shuttling to nucleus for SOX2 transcription. HCMV tegument protein pp71 dysregulates Notch signaling by altering the subcellular localization of the ligand Jag1 and NICD1 and promoting their degradation through proteasome. In addition, two important genes (Hes1 and SOX2) in development of inner ear are regulated by HCMV IE1: IE1 promotes Hes1 degradation and sequesters unphosphorylated STAT3 in the nucleus, both of which contribute to decreased SOX2 transcription.

Figure 4

Molecules in the Wnt and Notch signaling pathways participate in cell fate determination during the inner ear development. Expressing Dll1 and Neurog1 on otic placode (blue) drives cell differentiating into neuroblasts, while Jag1 and Sox2 promote prosensory specification (pink). Later, Notch pathway (Dll1/Jag2) and Wnt pathway (β-catenin/GSK3) cooperate to drive hair cell (cyan) fate; but in the surrounding cells, Notch signaling targets Hes1, Hes5 and Hey1 to direct the supporting cell (purple) fate.