Structure and function of vimentin in the generation and secretion of extracellular vimentin in response to inflammation

Abstract

The canonical functions of vimentin in cell mechanics and migration have been recently expanded by the discovery of new roles for extracellular vimentin (ECV) in immune responses to infection, injury and cancer. In contrast with the predominantly filamentous form of intracellular vimentin, ECV exists largely as soluble oligomers. The release of ECV from intact cells is dependent on mechanisms that regulate the assembly and disassembly of intracellular vimentin, which are influenced by discrete post-translational modifications. In this review we highlight the processes that promote the conversion of intracellular and insoluble vimentin filaments to ECV and secretion mechanisms. Insights into the regulation of ECV release from stromal and immune cells could provide new diagnostic and therapeutic approaches for assessing and controlling inflammatory diseases.

Keywords: Extracellular vimentin (ECV); Inflammation; Post-translational modifications (PTMs); Unconventional protein secretion (UPS); Vimentin.

Fig. 1

Dynamic conformational changes of vimentin. Typically, vimentin monomers assemble into filaments, which extend from the nuclear to the plasma membrane. Around the nucleus, vimentin filaments form a cage-like network. During cell spreading and adhesion, vimentin forms dot-like structures or squiggles that extend to the periphery of the cell and are considered as precursors of new filaments. Under certain conditions, increased vimentin solubility manifests as diffuse patterns. These localized pools of soluble vimentin could reassemble at distinct cellular locales and potentially be secreted outside the cell

Fig. 2

Structure of the vimentin molecule. Similar to other type III intermediate filaments, vimentin consists of a highly conserved central α-helical rod domain (312 amino acids) flanked by a head domain (95 amino acids) and a tail domain (59 amino acids). The head and tail domains are inherently disordered. (Information from Uniprot [66]). Vimentin undergoes various PTMs, including phosphorylation, glycosylation, and ADP-ribosylation in its head and tail domains, and glutathionylation of Cys328 in the rod domain (arrow). These modifications enable important regulatory mechanisms that dictate the assembly, disassembly, and overall functions of vimentin filaments

Fig. 3

Assembly and disassembly of vimentin IFs. Vimentin monomers initially combine (top of figure) to form coiled-coil dimers that subsequently assemble into antiparallel tetramers. Eight soluble tetramers associate laterally, creating unit-length filaments (ULFs). By longitudinal fusion driven by ‘head-to-tail’ interactions, ULFs combine to form insoluble, mature vimentin filaments (diameter: 10–12 nm). Mature filaments can undergo disassembly into more soluble polymers, which depends on regulation by different post-translational modifications (PTMs). Assembly and disassembly are dynamic processes that enable adaptation to alterations in cellular physiological states and external environmental stressors. PTMs such as glycosylation and acetylation promote vimentin filament stability while other PTMs such as citrullination, phosphorylation, sumoylation, ADP-ribosylation and glutathionylation enhance filament disassembly and ultimately, the generation of more solution vimentin

Fig. 4

The classical protein secretory pathway (ER-Golgi secretory pathway) and four types of unconventional protein secretion (UPS) pathways