Intermediate filament network perturbation in the C. elegans intestine causes systemic toxicity

Intermediate filaments (IFs) are major components of the metazoan cytoskeleton. A long-standing debate concerns the question whether IF network organization only reflects or also determines cell and tissue function. Using C. elegans , we have recently described mutants of the MAPK SMA-5, which perturb the organization of the intestinal IF cytoskeleton resulting in luminal widening and cytoplasmic invaginations. Besides these structural phenotypes, systemic dysfunctions were also observed. We now identify the IF polypeptide IFB-2 as a highly efficient suppressor of both the structural and functional deficiencies by removing the aberrant IF network. Mechanistically, IF network morphogenesis is linked to the phosphorylated IFB-2 aminoterminus. The rescuing capability is IF isotype-specific and not restricted to SMA-5 mutants but extends to other regulators of IF network morphogenesis, i.e. the cytoskeletal linker IFO-1 and the IF-associated protein BBLN1. The findings provide strong evidence for a gain-of-toxic function of the deranged IF networks with implications for diseases that are characterized by altered IF network organization.