Multilayered regulation of cytoskeletal protein abundance: autoregulatory mechanisms of actin and tubulin

Structural proteins such as actin and tubulin form the fundamental framework of the cytoskeleton and are essential for diverse cellular processes, including morphogenesis, intracellular transport and cell division. Maintaining precise intracellular levels is crucial for cellular homeostasis because both excess and deficiency can lead to cytotoxicity. Although transcriptional regulation establishes basal expression levels, recent studies have highlighted the crucial role of post-transcriptional and post-translational mechanisms in the fine-tuning of cytoskeletal protein abundance in response to dynamic cellular demands. Actin and tubulin use distinct autoregulatory strategies. Tubulin mRNA undergoes cotranslational decay, mediated by TTC5 and tightly regulated by the CARM1-PI3KC2α axis, linking ribosome-associated quality control with post-translational modifications. Conversely, actin regulation involves mRNA localization via ZBP1 and spatially restricted translation, coupled with a G-actin-MRTF/SRF transcriptional feedback loop. In addition, the ubiquitin-proteasome system modulates cytoskeletal protein turnover and fine-tunes microtubule dynamics. The dysregulation of these pathways has been implicated in various human diseases, including tubulinopathies, cancer and myopathies. In this Review, we summarize the multilayered regulatory networks that control actin and tubulin abundance, highlight recent advances in autoregulatory circuits and their disease relevance, and discuss future research directions for the therapeutic targeting of cytoskeletal proteostasis.