The dynamic regulation of the plasma membrane (PM) organization at the nanoscale emerged as a key element shaping the outcome of host-microbe interactions. Protein organization into nanodomains (ND) is often assumed to be linked to the activation of cellular processes. In contrast, we have previously shown that the phosphorylation of the Solanum tuberosum REM1.3 (StREM1.3) N-terminal domain disperses its native ND organization and promotes its inhibitory effect on Potato Virus X (PVX) cell-to-cell movement. Here, we show that the phosphorylation of StREM1.3 modify the chemical environment of numerous residues in its intrinsically-disordered N-terminal domain. We leveraged exploratory screens to identify potential phosphorylation-dependent interactors of StREM1.3. Herewith, we uncovered uncharacterized regulators of PVX cell-to-cell movement, linking StREM1.3 to autophagy, water channels and the actin cytoskeleton. We show that the Solanum tuberosum actin depolymerizing factors 2 (StADF2) alters StREM1.3 NDs and limits PVX cell-to-cell movement in a REMORIN-dependent manner. Mutating a conserved single residue reported to affect ADFs affinity to actin inhibits StADF2 effect on StREM1.3 ND organization and PVX cell-to-cell movement. These observations provide functional links between the organization of plant PM and the actin cytoskeleton and suggests that the alteration of StREM1.3 ND organization promotes plant anti-viral responses. We envision that analogous PM re-organization applies for additional signaling pathways in plants and in other organisms.
BACKGROUND & AIMSß-catenin is a well-known effector of the Wnt pathway and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of ß-catenin are highly frequent in pediatric liver primary tumors. Those mutations are mostly heterozygous allowing the co-expression of wild-type (WT) and mutated ß-catenins in tumor cells. We investigated the interplay between WT and mutated ß-catenins in liver tumor cells, and searched for new actors of the ß-catenin pathway.METHODSUsing an RNAi strategy in ß-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, carried mainly by, respectively, WT and mutated proteins. Their impact was characterized using transcriptomic and functional analyses. We studied mice that develop liver tumors upon activation of ß-catenin in hepatocytes (APCKO and ß-cateninΔexon3 mice). We made use of transcriptomic data from mouse and human HB specimens and analyzed samples by immunohistochemistry.RESULTSWe highlighted an antagonist role of WT and mutated ß-catenins on hepatocyte differentiation as attested by alteration of hepatocyte markers expression and bile canaliculi formation. We characterized Fascin-1 as a target of ß-catenin involved in hepatocyte differentiation. Using mouse models that allow the formation of two phenotypically distinct tumors (differentiated or undifferentiated), we found that Fascin-1 expression is higher in undifferentiated tumors. Finally, we found that Fascin-1 is a specific marker of the embryonal component in human HBs.CONCLUSIONSIn mice and human, Fascin-1 expression is linked to loss of differentiation and polarity of hepatocytes. Thus, we highlighted Fascin-1 as a new player in the modulation of hepatocyte differentiation associated to ß-catenin pathway alteration in the liver.Data Transparency Statementstudy materials will be made available to other researchers upon request.
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