A Novel Role of the Ubiquitin Conjugating Enzyme, UBE2G2, in Regulation of Cell Shape and Movement

We report a novel function of the ubiquitin conjugating enzyme, UBE2G2, beyond its well-established role in endoplasmic reticulum (ER)-associated degradation (ERAD). We demonstrate UBE2G2 profoundly influences cell shape and motility. Inactive UBE2G2 induces significant cell elongation, independent of matrix stiffness, composition, or charge. Mutant cells showed reduced total actin stress fibers, with dominant cortical ventral stress fibers aligned along the long axis. Vinculin redistributed to ventral stress fibers, likely altering the actin-adhesion dynamics. Absence of prominent lamellipodia and polarized distribution of filopodia at cell extremities demonstrates a reduced capacity for isotropic spreading and shape change. This was supported by slow wound closure in mutant cells that displayed low persistence and displacement despite similar pathlength and speed as wildtype cells. Sequestration of wildtype UBE2G2 by AUP1 to the membrane fraction mimicked the elongated phenotype in control cells showing that the cytosolic pool of the enzyme is responsible for the observed phenotype. Our results that UBE2G2 inactivating mutations can lock cells into a polarized, high-tension state have direct implications for diseases with aberrant cell shape and mechano-transduction.