Regulation of Wnt/β-catenin signaling by herpesviruses

Figure 3 Human cytomegalovirus inhibits PARsylation activity of tankyrase 1 and 2 (PARP5a/b) to enhance infection. Regulation of Axin is the rate-limiting step in the assembly and function of the β-catenin destruction complex. PARsylation, a process driven by NAD⁺, marks Axin for proteasomal degradation, inhibiting β-catenin destruction complex formation resulting in β-catenin accumulation and transcription in the nucleus. HCMV infection causes inhibition of TNKS (PARP5a/b) PARsylation activity, which inhibits PARsylation of Axin and increases its stability. Further inhibition of TNKS PARsylation activity or knockdown of TNKS significantly aids in HCMV replication. An increase in stable Axin permits β-catenin destruction complex formation, increased β-catenin degradation, and subsequent inhibition of β-catenin-mediated transcription. HCMV: Human cytomegalovirus; NAD⁺: Nicotinamide adenine dinucleotide; PARsylation: Poly-ADP ribose modification; PARP5a/b: Poly-ADP ribose polymerase 5a/b; TNKS: Tankyrase 1 and 2 (PARP5a/b).