Abstract
Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.
Highlights
Post-translational protein regulation is an important mechanism that provides cells with rapid responses to changes in intra-and extracellular conditions (Lee & Yaffe, 2016)
Since several Wnt proteins are upregulated in colorectal cancer (TCGA, 2012; Voloshanenko et al, 2013), we assumed that an increase in Wnt proteins might affect the levels of the cargo receptor Evi, allowing the cells to adjust to the molecular requirements for Wnt secretion
The Wnt-regulated protein bands were specific for Evi since they were absent in Evi knockout (EviKO) HEK293T cells (Fig 1B; Appendix Fig S2)
Summary
Post-translational protein regulation is an important mechanism that provides cells with rapid responses to changes in intra-and extracellular conditions (Lee & Yaffe, 2016). ERAD is a specialized ubiquitin-proteasome system (UPS)-dependent process that prevents the secretion and aggregation of proteins that failed to fold or assemble appropriately (Vembar & Brodsky, 2008). In addition to its role in protein quality control of nascent polypeptides, ERAD has been implicated in regulating the abundance of mature proteins in response to changes in physiological conditions (Wiertz et al, 1996a,b; Sever et al, 2003; Brodsky & Fisher, 2008; Adle et al, 2009; Foresti et al, 2013; Avci et al, 2014; van den Boomen et al, 2014). Given the number of ubiquitin ligases present in the ER (Neutzner et al, 2011), the physiological role of regulatory ERAD is likely underestimated at present
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