Ubiquitin and its relatives as wizards of the endolysosomal system

Abstract

The endolysosomal system comprises a dynamic constellation of vesicles working together to sense and interpret environmental cues and facilitate homeostasis. Integrating extracellular information with the internal affairs of the cell requires endosomes and lysosomes to be proficient in decision-making: fusion or fission; recycling or degradation; fast transport or contacts with other organelles. To effectively discriminate between these options, the endolysosomal system employs complex regulatory strategies that crucially rely on reversible post-translational modifications (PTMs) with ubiquitin (Ub) and ubiquitin-like (Ubl) proteins. The cycle of conjugation, recognition and removal of different Ub- and Ubl-modified states informs cellular protein stability and behavior at spatial and temporal resolution and is thus well suited to finetune macromolecular complex assembly and function on endolysosomal membranes. Here, we discuss how ubiquitylation (also known as ubiquitination) and its biochemical relatives orchestrate endocytic traffic and designate cargo fate, influence membrane identity transitions and support formation of membrane contact sites (MCSs). Finally, we explore the opportunistic hijacking of Ub and Ubl modification cascades by intracellular bacteria that remodel host trafficking pathways to invade and prosper inside cells.

PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling

“…Activated EGFR undergoes internalization, degradation or recycling in the absence of ligand [31]. Ubiquitin serves as a sorting signal during the endocytosis of EGFR [32]. Recruitment of the E3 ubiquitin ligase c-Cbl to activated EGFR is a key event leading to receptor ubiquitylation.…”

p97/VCP Promotes the Recycling of Endocytic Cargo

“…The association of the ubiquitin-binding cofactor PLAA with REs ( Figure 5, C–F ) and the PLAA-dependent interaction between p97 and MYOF ( Figure 5, A and B ) suggest an involvement of the ubiquitin system. However, while the posttranslational modification with ubiquitin is a well-established sorting signal for the ESCRT-mediated internalization of endocytic cargo into ILVs ( Raiborg and Stenmark, 2009 ), no unifying model for the role(s) of the ubiquitin system in endocytic recycling has emerged yet ( Berlin et al. , 2023 ).…”

EGFR endocytosis: more than meets the eye

“…Ubiquitin serves as a sorting signal during the endocytosis of EGFR while also regulating endocytic proteins [ 6 ]. Ligand-activated and autophosphorylated EGFR binds to the E3 ubiquitin ligase, CBL (Casitas B-lineage lymphoma), and gets ubiquitinated, which is essential for clathrin-independent endocytosis (CIE) of EGFR internalization upon high EGF concentrations.…”