BAG3-mediated proteostasis at a glance

Klimek, Christina; Kathage, Barbara; Wördehoff, Judith; Höhfeld, Jörg

doi:10.1242/jcs.203679

Cited by 79 publications

(88 citation statements)

References 119 publications

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“…Previous studies demonstrate that BAG3 plays an essential role in protein quality control [17]. In muscle cells, BAG3 senses mechanical stress and exhibits a housekeeping function by facilitating the removal of unfolded or damaged filamin [18].…”

Section: Discussionmentioning

confidence: 99%

“…BAG3 contains multiple domains including a HSPA/HSP70 interaction (BAG) domain at its C terminus, a tryptophan-containing (WW) domain at its N terminus, 2 IPV domains which mediate the interaction with small heat shock proteins such as HSPB6 and HSPB8, and a prolinerich (PXXP) domain in the central region [16,17]. One of the important functions of BAG3 is to regulate selective autophagy via specific interactions with its partner proteins [17]. Previous studies have shown that the WW domain of BAG3 is required for autophagy induction in glioma cells and muscle cells [18,19].…”

Section: Introductionmentioning

confidence: 99%

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BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes

Tang

Zeidler

et al. 2019

Preprint

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A major cellular catabolic pathway in neurons is macroautophagy/autophagy, through which misfolded or aggregation-prone proteins are sequestered into autophagosomes that fuse with lysosomes, and are subsequently degraded. MAPT (microtubule associated protein tau) is one of the protein clients of autophagy. Given that accumulation of hyperphosphorylated MAPT contributes to the pathogenesis of Alzheimer disease and other tauopathies, decreasing endogenous MAPT levels has been shown to be beneficial to neuronal health in models of these diseases. A previous study demonstrated that the HSPA/HSP70 co-chaperone BAG3 (BCL2 associated athanogene 3) facilitates endogenous MAPT clearance through autophagy. These findings prompted us to further investigate the mechanisms underlying BAG3-mediated autophagy in the degradation of endogenous MAPT. Here we demonstrate for the first time that BAG3 plays an important role in autophagic flux in the neuritic processes of mature neurons (20-24 days in vitro [DIV]) through interaction with the post-synaptic cytoskeleton protein SYNPO (synaptopodin). Loss of either BAG3 or SYNPO impeded the fusion of autophagosomes and lysosomes predominantly in the post-synaptic compartment. A block of autophagy leads to accumulation of the autophagic receptor protein SQSTM1/p62 (sequestosome 1) as well as MAPT phosphorylated at Ser262 (p-Ser262). Furthermore, p-Ser262 appears to accumulate in autophagosomes at post-synaptic densities. Overall these data provide evidence of a novel role for the co-chaperone BAG3 in synapses. In cooperation with SYNPO, it functions as part of a surveillance complex that facilitates the autophagic clearance of MAPT p-Ser262, and possibly other MAPT species at the post-synapse. This appears to be crucial for the maintenance of a healthy, functional synapse.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes

Tang

Zeidler

et al. 2019

Preprint

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“…BAG3 initiates the degradation of misfolded, damaged and aggregation-prone proteins through CASA by interacting with diverse partner proteins ( Fig. 1A) [10,11,13,14,[27][28][29]31]. To further elucidate the BAG3 interactome, an hemagglutinin (HA) tagged form of the cochaperone was expressed in human HEK293T cells followed by BAG3 complex isolation and mass spectrometry, according to previously established procedures [51].…”

Section: Stk38 Interacts With Bag3mentioning

confidence: 99%

“…BAG3 initiates the degradation of misfolded, damaged and aggregation-prone proteins through chaperone-assisted selective autophagy (CASA) [8][9][10][11]. In neurons, BAG3-mediated autophagy contributes to the degradation of the Alzheimerassociated protein tau and pathological forms of Huntingtin and SOD1, which are causative agents of Huntington's disease and amyotrophic lateral sclerosis, respectively [8,[12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy

Klimek

Wördehoff

Jahnke

et al. 2018

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Chaperone-assisted selective autophagy (CASA) initiated by the cochaperoneBcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.Abbreviations: BAG3, BCL2-associated athanogene; CASA, chaperone-assisted selective autophagy; CHIP, carboxy terminus of HSP70 interacting protein; EPS, electrical pulse stimulation; GST, glutathione-S-transferase; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; STK38, serine/threonine protein kinase 38.

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“…For example, we observed significant changes in the expression of Bcl-2 associated athanogene (Bag) proteins, which increase client release from Hsp70 by accelerating nucleotide exchange at the ATP site of this folding chaperone, in both naïve (ON) and influenza challenged (OF) aged cells. Here, we observed a striking difference in the expression pattern of Bag3 (Fig 10A, lower panel, black arrow), which is involved in regulating autophagy pathways (14,(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77),…”

Section: Folding Components Differentially Regulated By Aging and Infmentioning

confidence: 92%

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Loguercio

Hutt

Campos

et al. 2019

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Aging is associated with an increased risk for the development of many diseases. This is exemplified by the increased incidence of lung injury, muscle dysfunction and cognitive impairment in the elderly following influenza infection. Because the infectious cycle of flu is dependent upon the properties of the host, we examined the proteome of alveolar macrophages (AM) and type 2 cells (AT2) obtained from young (3 months) and old (18 months) naïve mice and mice exposed to influenza A. Our proteomics data show that there is a maladaptive collapse of the proteostasis network (PN) and changes in mitochondrial pathways in the aged naïve AM and AT2 proteomes. The mitochondrial imbalance and proteostatic collapse seen in aged cells places an excessive folding burden on these cells, which is further exacerbated following exposure to influenza A. Specifically, we see an imbalance in Hsp70 co-chaperones involved in protein folding and Hsp90 co-chaperones important for stress signaling pathways that are essential for cellular protection during aging. The acute challenge of influenza A infection of young and aged AM and AT2 cells reveals that age-associated changes in the chaperome affect the ability of these cells to properly manage the infection and post-infection biology, contributing to cytotoxicity. We posit that proteomic profiling of individual cell type specific responses provides a high impact approach to pinpoint fundamental molecular relationships that may contribute to the susceptibility to aging and environmental stress, providing a platform to identify new targets for therapeutic intervention to improve resiliency in the elderly.

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BAG3-mediated proteostasis at a glance

Cited by 79 publications

References 119 publications

BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes

BAG3 and SYNPO (synaptopodin) facilitate phospho-MAPT/Tau degradation via autophagy in neuronal processes

The Hippo network kinase STK38 contributes to protein homeostasis by inhibiting BAG3-mediated autophagy

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

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