Abstract
The co-chaperone BAG3, in complex with the heat shock protein HSPB8, plays a role in protein quality control during mechanical strain. It is part of a multichaperone complex that senses damaged cytoskeletal proteins and orchestrates their seclusion and/or degradation by selective autophagy. Here we describe a novel role for the BAG3-HSPB8 complex in mitosis, a process involving profound changes in cell tension homeostasis. BAG3 is hyperphosphorylated at mitotic entry and localizes to centrosomal regions. BAG3 regulates, in an HSPB8-dependent manner, the timely congression of chromosomes to the metaphase plate by influencing the three-dimensional positioning of the mitotic spindle. Depletion of BAG3 caused defects in cell rounding at metaphase and dramatic blebbing of the cortex associated with abnormal spindle rotations. Similar defects were observed upon silencing of the autophagic receptor p62/SQSTM1 that contributes to BAG3-mediated selective autophagy pathway. Mitotic cells depleted of BAG3, HSPB8 or p62/SQSTM1 exhibited disorganized actin-rich retraction fibres, which are proposed to guide spindle orientation. Proper spindle positioning was rescued in BAG3-depleted cells upon addition of the lectin concanavalin A, which restores cortex rigidity. Together, our findings suggest the existence of a so-far unrecognized quality control mechanism involving BAG3, HSPB8 and p62/SQSTM1 for accurate remodelling of actin-based mitotic structures that guide spindle orientation.
Highlights
Heat shock proteins (HSP) are molecular chaperones with key roles within the so-called proteostasis network
We report a novel role for HSPB8 and BCL2-associated athanogene 3 (BAG3) during mitosis in mammalian cells that involves the autophagic receptor p62/SQSTM1
We show that a reduction of any protein within the HSPB8-BAG3-p62/SQSTM signaling axis impairs mitotic progression and chromosome segregation by affecting orientation of the mitotic spindle and assembly of mitotic-specific actin structures
Summary
Heat shock proteins (HSP) are molecular chaperones with key roles within the so-called proteostasis network. This network is composed of elaborate pathways that allow cells to protect their proteome from aggregation, facilitate the assembly of multi-components complexes, and maintain the integrity of cytoskeleton polymers by eliminating damaged components in response to a variety of stress [1, 2]. HSP detect misfolded proteins and facilitate their refolding, seclusion or degradation. Associations of HSP with co-chaperones allow them to be recruited to specific, yet unrelated biological processes [3] These processes share a requirement for dynamic assembly-disassembly of multiprotein complexes at a given location and time, which often involve protein conformational changes. A proteotoxic stress response typified by upregulation of HSP is proposed to characterize most human malignant cells that experience increased proteomic instability [5]
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