Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

Abstract

Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities.

Lifting the ban on nuclear import activates Gdown1-mediated modulation of global transcription and facilitates adaptation to cellular stresses

“…In addition, the controlling mechanisms for switching off the CAS activity remain unclear. Based on our findings, one reasonable hypothesis is that post translational modifications of the core arginines within CAS or possibly other amino acids nearby might facilitate this switch via causing a conformational change or affecting the interactions of GDOWN1 to its regulatory factors (illustrated in Figure 7D), which is similar to the reported cases in the literature (Ashida et al, 2022; Navarro-Lerida et al, 2021).…”

Overcoming the cytoplasmic retention of GDOWN1 modulates global transcription and facilitates stress adaptation

“…In addition, the controlling mechanisms for switching off the CAS activity remain unclear. Based on our findings, one reasonable hypothesis is that post translational modifications of the core arginines within CAS or possibly other amino acids nearby might facilitate this switch via causing a conformational change or affecting the interactions of GDOWN1 to its regulatory factors (illustrated in Figure 7D ), which is similar to the reported cases in the literature ( Ashida et al, 2022 ; Navarro-Lérida et al, 2021 ).…”

Insights Into the Properties, Biological Functions, and Regulation of USP21

“…Furthermore, NES and NLS are not determinants of protein subcellular localization. Protein post-translational modifications and binding to other proteins also function as switches that regulate protein subcellular localization ( Dostie et al, 2000 ; Gabay-Maskit et al, 2020 ; Aggarwal et al, 2021 ; Navarro-Lerida et al, 2021 ). Taking USP4 as an example: AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane ( Zhang et al, 2012 ), while the binding of USP4 to Sart3 efficiently promotes its nuclear translocation ( Song et al, 2010 ).…”