A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism

Ganassi, Massimo; Matějů, Daniel; Bigi, Ilaria; Mediani, Laura; Poser, Ina; Lee, Hyun O.; Seguin, Samuel J.; Morelli, Federica; Vinet, Jonathan; Leo, Giuseppina; Pansarasa, Orietta; Cereda, Cristina; Poletti, Angelo; Alberti, Simon; Carra, Serena

doi:10.1016/j.molcel.2016.07.021

Cited by 261 publications

(365 citation statements)

References 41 publications

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“…Interestingly, several ribosomal and other RNA-binding proteins were also identified as part of the cardiac-specific BAG3 complex. Although unpredicted, these results support a recently described role for the BAG3-HSP70-HSPB8 complex in processing stress granules and defective ribosomal products, which may represent an underappreciated aspect of protein quality control (43). The remaining identified interactors were a variety of cytoplasmic, sarcomeric, nuclear, and secreted proteins that could be targets of the BAG3 chaperone complex, or they suggest a link to other cellular functions.…”

Section: Resultssupporting

confidence: 75%

“…Rigorous biochemical studies demonstrate that BAG3 acts as a co-chaperone by linking the HSP70 and HSPB families and modulating their function (18,22), while cellular experiments support the activity of a BAG3-HSP70-HSPB ternary complex (23,43). Using AP-MS, we identified specific proteins in the HSP70 and small HSP families that interact with BAG3 in cardiomyocytes, which are also coregulated by proteotoxic stress.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

Judge¹,

Pérez-Bermejo²,

Truong³

et al. 2017

JCI Insight

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Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 94%

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

Judge¹,

Pérez-Bermejo²,

Truong³

et al. 2017

JCI Insight

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“…The intermolecular interactions that regulate granule maturation and formation of fibrillar and amyloid-like structures are not fully understood, but several factors may contribute, including molecular chaperones and high RBP concentrations within liquid-like droplets (16,49). Using STED superresolution microscopy, we see clear enrichment of endogenous TDP-43 in the proximal axon compared with the mid axon and a similar density gradient in neurons expressing EGFP-TDP-43 ( Fig.…”

Section: Discussionmentioning

confidence: 91%

Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons

Gopal

Nirschl

Klinman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

229

247

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Ribonucleoprotein (RNP) granules are enriched in specific RNAs and RNA-binding proteins (RBPs) and mediate critical cellular processes. Purified RBPs form liquid droplets in vitro through liquid-liquid phase separation and liquid-like non-membrane-bound structures in cells. Mutations in the human RBPs TAR-DNA binding protein 43 and RNA-binding protein FUS cause amyotrophic lateral sclerosis (ALS), but the biophysical properties of these proteins have not yet been studied in neurons. Here, we show that TDP-43 RNP granules in axons of rodent primary cortical neurons display liquid-like properties, including fusion with rapid relaxation to circular shape, shear stress-induced deformation, and rapid fluorescence recovery after photobleaching. RNP granules formed from wild-type TDP-43 show distinct biophysical properties depending on axonal location, suggesting maturation to a more stabilized structure is dependent on subcellular context, including local density and aging. Superresolution microscopy demonstrates that the stabilized population of TDP-43 RNP granules in the proximal axon is less circular and shows spiculated edges, whereas more distal granules are both more spherical and more dynamic. RNP granules formed by ALS-linked mutant TDP-43 are more viscous and exhibit disrupted transport dynamics. We propose these altered properties may confer toxic gain of function and reflect differential propensity for pathological transformation.TDP-43 | ribonucleoprotein granules | liquid droplets | amyotrophic lateral sclerosis | neurons C ellular organelles allow eukaryotic cells to organize biochemical processes and concentrate specific cellular reactions in space and time. Although the role of membrane-bound organelles in cytoplasmic compartmentalization has long been recognized, the distinct biophysical properties and functions of non-membrane-bound organelles enriched in RNA and proteins have been recognized only recently (1-5). Ribonucleoprotein (RNP) granules, such as P granules in Caenorhabditis elegans (1), nucleoli in Xenopus laevis oocytes (2), yeast P bodies (3), and mammalian stress granules (6), show liquid droplet properties (reviewed in refs. 5, 7, 8), including fusion with rapid relaxation to a spherical shape, dynamic internal rearrangements, and rapid dissolution and assembly. Proteins comprising RNP granules share a common structure containing both RNA recognition motifs (RRMs) and low-complexity sequences (LCSs), intrinsically disordered regions that mediate protein-protein interactions (7, 9). In vitro characterization of human RNP granule proteins, RNA-binding protein FUS and heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which are mutated in rare inherited forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (10-12), has revealed the LCS drives self-assembly of RNP granules through a process termed liquid-liquid phase separation (LLPS) (6, 13-18).Among eukaryotic cells, neurons face unique challenges in spatiotemporal cytoplasmic organization related to their com...

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“…While BAG3 controls the stability of HSPB8, it may also function without HSPB8 during stress, questioning the exact role of HSPB8 in the reported functions of BAG3 (our unpublished data) (Ganassi et al 2016;Minoia et al 2014). Recently, we uncovered an HSPB8-dependent function of BAG3 in a basic and fundamental activity of cancer cells: mitosis, in the remodeling of actinbased structures that guide spindle dynamics ).…”

Section: Discussionmentioning

confidence: 94%

Fine-tuning of actin dynamics by the HSPB8-BAG3 chaperone complex facilitates cytokinesis and contributes to its impact on cell division

Varlet

Fuchs

Luthold

et al. 2017

Cell Stress and Chaperones

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The small heat shock protein HSPB8 and its cochaperone BAG3 are proposed to regulate cytoskeletal proteostasis in response to mechanical signaling in muscle cells. Here, we show that in dividing cells, the HSPB8-BAG3 complex is instrumental to the accurate disassembly of the actin-based contractile ring during cytokinesis, a process required to allow abscission of daughter cells. Silencing of HSPB8 markedly decreased the mitotic levels of BAG3 in HeLa cells, supporting its crucial role in BAG3 mitotic functions. Cells depleted of HSPB8 were delayed in cytokinesis, remained connected via a disorganized intercellular bridge, and exhibited increased incidence of nuclear abnormalities that result from failed cytokinesis (i.e., bi-and multi-nucleation). Such phenotypes were associated with abnormal accumulation of F-actin at the intercellular bridge of daughter cells at telophase. Remarkably, the actin sequestering drug latrunculin A, like the inhibitor of branched actin polymerization CK666, normalized F-actin during cytokinesis and restored proper cell division in HSPB8-depleted cells, implicating deregulated actin dynamics as a cause of abscission failure. Moreover, this HSPB8-dependent phenotype could be corrected by rapamycin, an autophagy-promoting drug, whereas it was mimicked by drugs impairing lysosomal function. Together, the results further support a role for the HSPB8-BAG3 chaperone complex in quality control of actin-based structure dynamics that are put under high tension, notably during cell cytokinesis. They expand a so-far underappreciated connection between selective autophagy and cellular morphodynamics that guide cell division.

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A Surveillance Function of the HSPB8-BAG3-HSP70 Chaperone Complex Ensures Stress Granule Integrity and Dynamism

Cited by 261 publications

References 41 publications

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons

Fine-tuning of actin dynamics by the HSPB8-BAG3 chaperone complex facilitates cytokinesis and contributes to its impact on cell division

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