Intermediate filaments and IF-associated proteins: from cell architecture to cell proliferation

Abstract

Intermediate filaments (IFs), in coordination with microfilaments and microtubules, form the structural framework of the cytoskeleton and nucleus, thereby providing mechanical support against cellular stresses and anchoring intracellular organelles in place. The assembly and disassembly of IFs are mainly regulated by the phosphorylation of IF proteins. These phosphorylation states can be tracked using antibodies raised against phosphopeptides in the target proteins. IFs exert their functions through interactions with not only structural proteins, but also non-structural proteins involved in cell signaling, such as stress responses, apoptosis, and cell proliferation. This review highlights findings related to how IFs regulate cell division through phosphorylation cascades and how trichoplein, a centriolar protein originally identified as a keratin-associated protein, regulates the cell cycle through primary cilium formation.

Keywords: cell proliferation; cytokinesis; intermediate filament; post-translational modification; primary cilium; site- and phosphorylation state-specific antibody.

Figure 1.

Compromised IF phosphorylation leads to defective cytokinesis, tetraploidy, and aneuploidy. From anaphase to telophase, Rho kinase and Aurora B kinase phosphorylate type III IFs, leading to local IF depolymerization and cytokinesis. When this phosphorylation is compromised, unusual long bridge-like IF structures are formed, leading to cytokinetic failure and tetraploidy, a condition in which cells have four homologous sets of chromosomes. Mitosis of tetraploid cells frequently causes lagging chromosomes through merotelic attachment, resulting in aneuploidy, a deviation from a multiple of the haploid chromosome number in which some of the chromosomes are missing or present in excess. Aneuploidy is frequently observed in cancer cells and senescent cells.

Figure 2.

Trichoplein promotes cell proliferation through suppression of ciliogenesis in the presence of EGF. A) EGF activates USP8 through phosphorylation. Activated USP8 deubiquitinates and stabilizes trichoplein at the mother centriole. Trichoplein suppresses ciliogenesis through activation of Aurora A kinase, which stimulates cell proliferation. B) In the absence of EGF signaling, USP8 is not activated. Unphosphorylated USP8 (inactive USP8) allows for the polyubiquitination of TCHP by CRL3-KCTD17, which culminates in TCHP degradation and primary cilium formation. Cell cycle arrest occurs after formation of the primary cilium.