Hsp70 proteins in mitosis and disease

Heat shock proteins (HSPs) are ATP-dependent molecular chaperones which aid folding of nascent polypeptides, maintain proteins in unstable conformations and prevent protein denaturation. These functions are essential in many biological contexts, including assembly and disassembly of macromolecular complexes, trafficking of proteins and regulation of enzyme activity [1]. Mitotic cell division is particularly complex involving rapid changes in cytoskeletal and organelle architecture. One would therefore expect it to be highly dependent on HSPs; however, much remains to be learnt about the roles of HSPs in mitosis. In a recent study, we discovered that Hsp72, an inducible cytoplasmic isoform of the Hsp70 family, is essential to build a mitotic spindle capable of efficient chromosome congression and segregation [2]. Firstly, Hsp72 contributes to generation of stable kinetochore (K)-fibres. K-fibres are bundles of microtubules that connect the spindle poles with the kinetochores and are essential for chromosome movement. Upon depletion of Hsp72 or addition of an Hsp70 inhibitor, cells exhibited reduced K-fibres. This was coincident with misaligned chromosomes, metaphase delay and a strongly active spindle assembly checkpoint. The loss of K-fibres was not caused by reduction in microtubule nucleation, but rather failure to recruit the K-fibre-stabilising proteins, ch-TOG and TACC3. Hsp72 localises to spindle poles and spindle fibres in a similar manner to ch-TOG and TACC3. Furthermore, when TACC3 was immunoprecipitated from cells treated with the Hsp70 inhibitor, association with its partner, ch-TOG, was reduced. Together, this suggests that Hsp72 stabilises K-fibres by facilitating assembly of ch-TOG and TACC3 into a complex that can then serve to bundle K-fibre microtubules [3]. Secondly, abrogation of Hsp72 function led to reduced interpolar distances, reduced astral microtubules and misoriented spindles. Astral microtubules attach the spindle to the cell cortex to maintain its shape and position. These data indicate that Hsp72 has additional functions in astral microtubule organization or cortical attachment. This is likely to be independent of the ch-TOG-TACC3 complex as this is not thought to be required for astral microtubule function. Importantly, whilst Hsp72 depletion and chemical inhibition of Hsp70 give similar phenotypes, there are some clear differences. This can be explained by that fact that chemical inhibition blocks the activity of all Hsp70 isoforms and it is possible that other Hsp70 isoforms have roles in mitosis. On the other hand, chemical inhibition does not remove the protein and so the different phenotypes may result from Hsp72 having mitotic functions as a scaffold that are independent …