SUMMARY The WNT signaling network is comprised of multiple receptors that relay various input signals via distinct transduction pathways to execute multiple complex and context-specific output processes. Integrity of the WNT signaling network relies on proper specification between canonical and noncanonical pathways, which presents a regulatory challenge given that several signal transducing elements are shared between pathways. Here, we report that USP9X, a deubiquitylase, and WWP1, an E3 ubiquitin ligase, regulate a ubiquitin rheostat on DVL2, a WNT signaling protein. Our findings indicate that USP9X-mediated deubiquitylation of DVL2 is required for canonical WNT activation, while increased DVL2 ubiquitylation is associated with localization to actin-rich projections and activation of the planar cell polarity (PCP) pathway. We propose that a WWP1-USP9X axis regulates a ubiquitin rheostat on DVL2 that specifies its participation in either canonical WNT or WNT-PCP pathways. These findings have important implications for therapeutic targeting of USP9X in human cancer.

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Maturation of the vaccinia virion is an intricate process that results in the organization of the viroplasm contained in immature virions into the lateral bodies, core wall and nucleocapsid observed in the mature particles. It is unclear how this organization takes place and studies with mutants are indispensable in understanding this process. By characterizing an inducible mutant in the A3L gene, we revealed that A3, an inner core wall protein, is important for formation of normal immature viruses and also for the correct localization of L4, a nucleocapsid protein. L4 did not accumulate in the viral factories in the absence of A3 and was not encapsidated in the particles that do not contain A3. These data strengthen our previously suggested hypothesis that A3 and L4 interact and that this interaction is critical for proper formation of the core wall and nucleocapsid.

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1The WNT signaling network is comprised of multiple receptors that relay various input 2 signals via distinct transduction pathways to execute multiple complex and context-specific 3 output processes. Integrity of the WNT signaling network relies on proper specification between 4 canonical and non-canonical pathways, which presents a regulatory challenge given that 5 several signal transducing elements are shared between pathways. Here, we report that 6 USP9X, a deubiquitylase, and WWP1, an E3 ubiquitin ligase, regulate a ubiquitin rheostat on 7 DVL2, a WNT signaling protein. Our findings indicate that USP9X-mediated deubiquitylation of 8 DVL2 is required for canonical WNT activation, while increased DVL2 ubiquitylation is 9 associated with localization to actin-rich projections and activation of the planar cell polarity 10 (PCP) pathway. We propose that a WWP1-USP9X axis regulates a ubiquitin rheostat on DVL2 11 that specifies its participation in either canonical WNT or WNT-PCP pathways. These findings 12 have important implications for therapeutic targeting of USP9X in human cancer. 13 Nielsen et al.3