Vimentin provides the mechanical resilience required for amoeboid migration and protection of the nucleus

Abstract

statement (short abstract 40 words):Vimentinin joint action with actinmediates the mechanical stiffness of cells required for amoeboid cell migration through confined spaces and protects the nucleus from DNA damage. AbstractDendritic cells use amoeboid migration through constricted passages to reach the lymph nodes, and this homing function is crucial for immune responses. Amoeboid migration requires mechanical resilience, however, the underlying molecular mechanisms for this type of migration remain unknown. Because vimentin intermediate filaments (IFs) and microfilaments regulate adhesion-dependent migration in a bidirectional manner, we analyzed if they exert a similar control on amoeboid migration. Vimentin was required for cellular resilience, via a joint interaction between vimentin IFs and F-actin. Reduced actin mobility in the cell cortex of vimentin-reduced cells indicated that vimentin promotes Factin subunit exchange and dynamics. These mechano-dynamic alterations in vimentindeficient dendritic cells impaired amoeboid migration in confined environments in vitro and blocked lymph node homing in mouse experiments in vivo. Correct nuclear positioning is important in confined amoeboid migration both to minimize resistance and to avoid DNA damage. Vimentin-deficiency also led to DNA double strand breaks in the compressed dendritic cells, pointing to a role of vimentin in nuclear positioning. Together, these observations show that vimentin IF-microfilament interactions provide both the specific mechano-dynamics required for dendritic cell migration and the protection the genome needs in compressed spaces.

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

“…Due to the numerous roles of vimentin, the effect of vimentin inhibition in non-malignant cells should be considered. To this end, consequences of its inhibition should be studied in animal models and effects on processes entailing cell migration (such as wound healing [73,133] or immune response [87,134]) should be carefully examined. However, since mice lacking vimentin develop and reproduce without any major problem [135], we can anticipate that beneficial vimentin inhibition in malignant cells outweighs any potential adverse effects.…”

“…It was recently shown that vimentin regulates nuclear shape and volume and protects the nucleus from DNA damage during invasion in confined environments. In amoeboid dendritic cells, vimentin IFs along with actin filaments were necessary for protection of the nucleus during confined migration, and loss of vimentin resulted in defective migration [87]. However, in mouse embryonic fibroblasts, the absence of vimentin IFs promoted migration through small pores [88].…”

A flexible network of Vimentin intermediate filaments promotes the migration of amoeboid cancer cells through confined environments

“…Vimentin may be particularly important for protecting the nucleus from compressive force, as several adaptor proteins have been reported to connect it to the nuclear envelope (25)(26)(27). Accordingly, Vimentin has been recently reported to protect the nucleus from rupture and DNA damage in confinement (28,29). In line with these results, we find the nucleus in Vimentin RNAi cells to undergo dramatic shape changes during LBBM.…”

Intermediate Filaments as Potential Target for Cancer 2 Treatment

“…It was recently shown that vimentin regulates nuclear shape and volume and protects the nucleus from DNA damage during invasion in confined environments. In amoeboid dendritic cells, vimentin IFs along with actin filaments were necessary for protection of the nucleus during confined migration, and loss of vimentin resulted in defective migration [86]. However, in mouse embryonic fibroblasts, the absence of vimentin IFs promoted migration through small pores [87].…”