ISG15 and ISGylation:Emergence in the cytoskeleton dynamic and tumor microenvironment

Cytoskeletal remodeling affects the shape,adhesion,and motility of cells.Cytoskeletal dynamics are modulated by matrix proteins,integrins,and several cytokines in the tumor microenvironment.In this scenario,signaling is activated by integrins and interferons,which can induce ISG15 gene expression.This gene encodes a ubiquitin-like protein that functions as a protein modifier via the ISGylation system.Furthermore,non-conjugated ISG15 acts as a cytokine-like protein.In this viewpoint,the interplay between free ISG15,protein ISGylation,and cytoskeletal dynamics in the tumor microenvironment is discussed.

Transcriptional cofactors Ski and SnoN are major regulatorsof the TGF-β/Smad signaling pathway in health and disease

The transforming growth factor-β(TGF-β)family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis.The TGF-βsignaling pathway outcome relies on the control of the spatial and temporal expression of>500 genes,which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway,such as transcriptional factors and cofactors.Ski(Sloan-Kettering Institute)and SnoN(Ski novel)are Smadinteracting proteins that negatively regulate the TGF-βsignaling pathway by disrupting the formation of R-Smad/Smad4 complexes,as well as by inhibiting Smad association with the p300/CBP coactivators.The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription.The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms.Thus,these cross-regulatory processes finely modify the TGF-βsignaling outcome as they control the magnitude and duration of the TGF-βsignals.As a result,any alteration in these regulatory mechanisms may lead to disease development.Therefore,the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-βpathway,such as Ski and SnoN,is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated,such as fibrosis and cancer.