Hydrogel formation by multivalent IDPs: A reincarnation of the microtrabecular lattice?

Based on high-voltage electron microscopic (HVEM) data of fixed cultured cells, an elaborate three-dimensional network of filaments, including and interconnecting other elements of the cytoskeleton, was observed in cells some half a century ago. Despite many attempts and comparative studies, this “microtrabecular lattice” (MTL) of the cytoplasmic ground substance could not be established as a genuine component of the eukaryotic cell, and is mostly considered today as a sample-preparation artifact of protein adherence and cross-linking to the cytoskeleton. Here we elaborate on the provocative idea that recent observations of hydrogel-forming phase transitions of repetitive regions of intrinsically disordered proteins (IDPs) bear resemblance in creation, organization and physical appearance to the MTL. We review this phenomenon in detail, and suggest that phase transitions of actin regulatory proteins, neurofilament side-arms and other proteins could generate non-uniform spatial distribution of cytoplasmic material in the vicinity of the cytoskeleton that might even give rise to fixation phenomena resembling the MTL. Whether such hydrogel formation by IDPs is a general physical phenomenon, will remain to be seen, nevertheless, the underlying organizational principle provokes novel experimental studies to uncover the ensuing higher-level regulation of cell physiology, in which the despised and long-forgotten concept of MTL might give some interesting leads.