Type III intermediate filaments in redox interplay: key role of the conserved cysteine residue

Abstract

Intermediate filaments (IFs) are cytoskeletal elements involved in mechanotransduction and in the integration of cellular responses. They are versatile structures and their assembly and organization are finely tuned by posttranslational modifications. Among them, type III IFs, mainly vimentin, have been identified as targets of multiple oxidative and electrophilic modifications. A characteristic of most type III IF proteins is the presence in their sequence of a single, conserved cysteine residue (C328 in vimentin), that is a hot spot for these modifications and appears to play a key role in the ability of the filament network to respond to oxidative stress. Current structural models and experimental evidence indicate that this cysteine residue may occupy a strategic position in the filaments in such a way that perturbations at this site, due to chemical modification or mutation, impact filament assembly or organization in a structure-dependent manner. Cysteine-dependent regulation of vimentin can be modulated by interaction with divalent cations, such as zinc, and by pH. Importantly, vimentin remodeling induced by C328 modification may affect its interaction with cellular organelles, as well as the cross-talk between cytoskeletal networks, as seems to be the case for the reorganization of actin filaments in response to oxidants and electrophiles. In summary, the evidence herein reviewed delineates a complex interplay in which type III IFs emerge both as targets and modulators of redox signaling.

Keywords: Alexander disease; cysteine modification; intermediate filaments; lipoxidation; oxidative stress; vimentin.

Figure 1.. Assembly and features of vimentin Intermediate filaments.

(A) Schematic cartoon displaying the features of the vimentin monomer with the head, rod and tail domains. The approximate position of C328 is denoted by a black circle. The assembly process of the filament with the formation of parallel dimers, association into antiparallel tetramers and their organization into unit length filaments (ULFs) is schematically shown. Connection of several ULFs will lead to filament formation. In this process, cysteine residues from different subunits could putatively coincide near the region of overlap (encircled by the yellow oval). Please note that this representation does not intend to be structurally accurate. Elements of this panel were adapted from Monico et al. [75], published under CC BY license. (B) Model obtained from the cryoelectron tomography structure of vimentin filaments in mouse embryonic fibroblasts [30], highlighting the position of the cysteine residues (yellow). Courtesy of Prof. O. Medalia. See text for details.

Figure 2.. Modifications of the single cysteine residues of desmin, GFAP and vimentin.

The type III intermediate filament proteins that possess a single cysteine residue fully conserved between species are shown at the left. These cysteine residues are hot spots for PTMs. Various types of lipoxidative and oxidative modifications, as well as modifications by chemicals, natural products and drug metabolites, shown in boxes at right, have been identified, mainly in the case of vimentin C328. These various modifications may elicit structure-dependent functional consequences.