Impact of RSUME Actions on Biomolecular Modifications in Physio-Pathological Processes

FUERTES, MARIANA; ELGUERO, BELÉN; GONILSKI-PACIN, DAVID; HERBSTEIN, FLORENCIA; ROSMINO, JOSEFINA; CIANCIO DEL GIUDICE, NICOLAS; FIZ, MANUEL; FALCUCCI, LARA; ARZT, EDUARDO

Frontiers in Endocrinology

Elsevier

Año: 2022 vol. 13

The small RWD domain-containing protein called RSUME or RWDD3 was cloned frompituitary tumor cells with increasing tumorigenic and angiogenic proficiency. RSUMEexpression is induced under hypoxia or heat shock and is upregulated, at severalpathophysiological stages, in tissues like pituitary, kidney, heart, pancreas, or adrenalgland. To date, several factors with essential roles in endocrine-related cancer appear tobe modulated by RWDD3. RSUME regulates, through its post-translational (PTM)modification, pituitary tumor transforming gene (PTTG) protein stability in pituitarytumors. Interestingly, in these tumors, another PTM, the regulation of EGFR levels byUSP8, plays a pathogenic role. Furthermore, RSUME suppresses ubiquitin conjugation tohypoxia-inducible factor (HIF) by blocking VHL E3-ubiquitin ligase activity, contributing tothe development of von Hippel-Lindau disease. RSUME enhances protein SUMOylationof specific targets involved in inflammation such as IkB and the glucocorticoid receptor.For many of its actions, RSUME associates with regulatory proteins of ubiquitin andSUMO cascades, such as the E2-SUMO conjugase Ubc9 or the E3 ubiquitin ligase VHL.New evidence about RSUME involvement in inflammatory and hypoxic conditions, suchas cardiac tissue response to ischemia and neuropathic pain, and its role in severaldevelopmental processes, is discussed as well. Given the modulation of PTMs by RSUMEin neuroendocrine tumors, we focus on its interactors and its mode of action. Insights intofunctional implications and molecular mechanisms of RSUME action on biomolecularmodifications of key factors of pituitary adenomas and renal cell carcinoma providerenewed information about new targets to treat these pathologies.