Microtubule Inner Proteins: a meshwork of luminal proteins fine-tuning the biophysical properties of the ciliary doublet

Abstract

Cilia are large macromolecular organelles at the surface of most eukaryotic cells. These evolutionary conserved structures generate coordinated beating motions that are critical for processes throughout the body such as fluid movement across tissues and cellular locomotion. At their core is a microtubule-based structure called the axoneme which serves as a structural framework to the cilia. The axoneme comprises radially disposed microtubule doublets around a central pair, providing mechanical support and enabling organelle motion. The axoneme endures significant mechanical stress due to the repeated beating of the cilia, requiring the doublets to maintain remarkable structural integrity. Early cryo-electron tomography studies of the axoneme revealed a non-tubulin protein sheath lining the inner walls of the microtubule doublet. These microtubule inner proteins (MIPs) are woven into the tubulin inner walls of both tubules in the microtubule doublets. To date, the role and function of these proteins in the microtubule doublet and the cilia are just starting to be explored. Emerging studies leveraging recent advancements in cryo-electron tomography map resolution have focused on identifying these proteins and understanding their functions. They were shown to be closely related to ciliopathies, a broad spectrum of diseases resulting from ciliary dysfunction. In this review, we summarize the current knowledge on ciliary MIPs within microtubule doublets, highlight recent progress in their identification, and explore their potential role in supporting ciliary function.