ESCRT and Membrane Protein Ubiquitination

Abstract

The ubiquitin-dependent degradation of membrane proteins via the multivesicular body (MVB) pathway requires the Endosomal Sorting Complexes Required for Transport (ESCRT). This molecular machinery is composed of five distinct multi-subunit complexes. On the surface of endosomes, ESCRT-0, -I and -II bind to ubiquitinated membrane proteins, while ESCRT-III and Vps4 bud intraluminal vesicles (ILVs) into the lumen of the endosomes. By working together, ESCRTs package membrane proteins into ILVs and thereby generate MVBs. The fusion of mature MVBs with lysosomes delivers ILVs into the lysosomal lumen where the membrane proteins are degraded. Besides generating ILVs, the ESCRT machinery mediates for topologically related membrane budding processes at the plasma membrane and the nuclear envelop. In this chapter, we briefly discuss membrane protein ubiquitination, endocytosis, and summarize current knowledge on the ESCRT machinery in the MVB pathway.

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…This is, in part, a calcium-regulated process that entails fusion of the lysosomal limiting membrane with the plasma membrane (Stinchcombe et al, 2004). Lysosomes can also transiently contain ILVs delivered from the MVB which are released into the extracellular space upon lysosomal exocytosis (Migliano and Teis, 2018). Dysfunction of the endosomal-lysosomal pathway in AD appears to cause lysosomal components to FIGURE 1 | Generation of intraluminal vesicles (ILVs) within MVBs in a neuron.…”

The importance of virion-incorporated cellular RNA-Binding Proteins in viral particle assembly and infectivity

“…The cellular endosomal sorting complex required for transport (ESCRT) is a large multi-component machinery comprised of five complexes, ESCRT-0, ESCRT-I, ESCRT-II, ESCRT-III and Vps4, which assemble sequentially in a multi-step manner following ubiquitination of ESCRT-0 [ 92 ]. The ESCRT machinery is hijacked for viral particle release across most types of viruses including retroviruses, filoviruses, arenaviruses, paramyxoviruses, rhabdoviruses, flaviviruses, reoviruses and picornaviruses [ 93 ].…”

EGAD ! There is an ERAD doppelganger in the Golgi

“…In post‐ER compartments, disposal of membrane proteins was thought to depend only on lysosomal degradation, through a process involving the ESCRT (endosomal sorting complexes required for transport) machinery (Migliano & Teis, ). Ubiquitinated membrane proteins at the surface of endosomes/multivesicular bodies (MVBs) are recognized by ESCRT complexes that promote their sorting and internalization into intraluminal vesicles, a process that also requires the AAA+ ATPase Vps4.…”

“…Ubiquitinated membrane proteins at the surface of endosomes/multivesicular bodies (MVBs) are recognized by ESCRT complexes that promote their sorting and internalization into intraluminal vesicles, a process that also requires the AAA+ ATPase Vps4. Subsequent MVB fusion with the lysosome results in the release of intraluminal vesicles in the hydrolytic lumen of the lysosome, and ultimately in the degradation of their content (Migliano & Teis, ).…”

“…In the absence of Rbd2, however, the Dsc complex targets the immature SREBP precursor for proteasomal degradation (Hwang et al, 2016). This observation is at odds with work in budding yeast, where Tul1 substrates appeared to be degraded exclusively via the lysosome (Migliano & Teis, 2018). Moreover, a recent study (Yang et al, 2018) describing two mutually exclusive Dsc cofactors, Vld1 and Gld1, has defined Dsc complexes with distinct subcellular distribution: While Gld1containing Dsc complexes localize to Golgi/ endosomes, Vld1-containing complexes are found at the membrane of the vacuole, the yeast equivalent of the lysosome (Yang et al, 2018).…”