Promoting ESCRT-I narcissism

Promoting ESCRT-I narcissism A new endosomal protein keeps ESCRT-I too wrapped up in itself to be attracted to anyone else, Chu et al. reveal on page 815. This matchbreaker prevents the premature assembly of the machinery that forms multivesicular bodies (MVBs). MVBs are endosomes with internal vesicles. The vesicles contain membrane proteins bound for fusion with lysosomes or viral particles hoping to escape from the cell. Vesicles bud internally from the endosomal membrane with help from three ESCRT complexes (I, II, and III) that are sequentially recruited from the cytosol to the endosome. Chu et al. found a new component that helps keep this recruitment in proper order. The helper is a small protein, which the authors call Mvb12, that binds to ESCRT-I and regulates its associations. With Mvb12, most ESCRT-I was found in stable cytoplasmic oligomers (probably trimers). Exactly how Mvb12 stabilizes the oligomers is not clear. The oligomerization seems to mask ESCRT-I’s binding site for ESCRT-II; in the absence of Mvb12, ESCRT-I was instead locked together with ESCRT-II, both in the cytoplasm and on endosomes. Their premature joining resulted in ineffi cient sorting into MVBs; much of the MVB cargo remained on the endosomal surface. The authors now want to understand how Mvb12 release is prompted to allow timely ESCRT-II binding. Encountering PI3P and ubiquitinated cargo on the endosome might release Mvb12, resulting in oligomer disassembly and ESCRT-II binding. The fi nal stages of MVB formation, including ESCRT-III recruitment, can then follow. Do-it-yourself insertion T he membrane insertion of eukaryotic proteins generally requires the assistance of other membrane proteins. But on page 767, Brambillasca et al. show that surprisingly long protein stretches get across membranes unassisted, as long as their transmembrane domains (TMD) are not too hydrophobic. Ancestral membrane proteins may have similarly self-inserted. The group started with a variant of cytochrome b(5), whose 28-residue luminal domain was known to push its way through protein-free liposomes. They now fi nd that b5 can push luminal domains of up to 85 residues through liposomes and into the ER of yeast cells lacking the normal translocation machinery. Unassisted translocation might also pick up the slack in normal eukaryotic cells when ER translocons are congested. A membrane protein of similar topology, called Syb2, had no such power. The authors traced the disparity to the TMD: the lower hydrophobicity of b5’s TMD was unexpectedly advantageous for insertion into liposomes. The authors imagine that more hydrophobic TMDs might aggregate in the cytoplasm as they are released from ribosomes, creating an unsuitable conformation for ER insertion. In vivo, however, chaperones might prevent this aggregation. Based on its low TMD hydrophobicity, the authors identifi ed the PTP1B phosphatase as another self-inserting protein. Unassisted insertion only works in low-cholesterol membranes, such as the ER and mitochondria, whose lipids are free to move around while proteins push through. The Golgi and plasma membrane, by contrast, are probably too rigid.