Microtubule organization in normal cells and disease: The housekeeping role of heat-shock proteins and immunophilins

Abstract

Cytoskeleton is the basic scaffold of the cell in which other subcellular components are spatially arranged, such that they are able to communicate efficiently between the internal and external environments of the cell. Cytoskeletal structure is continually remodeled to accommodate normal cell growth and to respond to pathophysiological cues. As a consequence, several cytoskeleton-interacting proteins become involved in a variety of cellular processes such as cell growth and division, cell movement, vesicle transportation, cellular organelle location and function, localization and distribution of membrane receptors, and cell-cell communication. Molecular chaperones and immunophilins are counted among the most important proteins that interact closely with the cytoskeleton network, in particular with microtubules and microtubule-associated factors. In several situations, chaperones and immunophilins work together as a functionally active heterocomplex, although both types of proteins also show independent actions. In circumstances where homeostasis is affected by environmental stresses or due to genetic alterations, chaperone proteins help to stabilize the system. Molecular chaperones facilitate the assembly, disassembly and/or folding/refolding of cytoskeletal proteins, so they prevent aberrant protein aggregation. Nonetheless, the role of chaperones is not limited to solve abnormal situations. They also have an active participation during the normal differentiation process of the cell and are key factors for many structural and functional rearrangements during this course of action. A similar observation is also valid for immunophilins. Although the folding system for microtubules was discovered nearly two decades ago, our understanding of the complex quality control pathway of these filaments is still poorly understood and there are many unanswered questions that remain to be elucidated. Microtubule modifications leading to altered localization nuclear factors may result in loss- or gain-of-function of such factors, which affects the cell cycle and cell development. Therefore, microtubules are attractive therapeutic targets, particularly to prevent pathological situations such as rapidly dividing tumors or to favor the process of cell differentiation in other cases. In this chapter we will address some mechanistic aspects of the key regulatory functions of heat-shock proteins and immunophilins in the microtubule network of neurons and cancer cells.