BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance

Lin, Heng; Tang, Maoping; Ji, Changyi; Girardi, Peter; Cvetojevic, Gregor; Chen, Daniel; Koren, Shon; Johnson, Gail V.W.

doi:10.1016/j.biopsych.2021.10.024

Cited by 17 publications

(14 citation statements)

References 74 publications

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“…In another study of tauopathy mice, increased farnesyl transferase activity to translocate the Rhes GTPase to autophagic vesicles was associated with low tau hyperphosphorylation, while inhibition of Rhes promoted tau hyperphosphorylation [ 115 ]. Thus, GTPase-dependent autophagy effectively clears pTau [ 116 ] and impaired autophagy from low GTP levels or oxidative redox state would impair clearance of pTau.…”

Section: Gtp-dependence Of Tubulin Assembly Vesicle Transport and Pro...mentioning

confidence: 99%

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

et al. 2023

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Increased interest in the aging and Alzheimer’s disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation.

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Section: Gtp-dependence Of Tubulin Assembly Vesicle Transport and Pro...mentioning

confidence: 99%

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

et al. 2023

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“…BAG3, through its interaction with TBC1D10B supports the activation of Rab35 and recruitment of Hrs, which initiates ESCRT‐mediated endosomal tau clearance. Intrahippocampal expression of BAG3 in P301S mice increased the co‐localization of phospho‐tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau 144 . In summary, these studies indicate a close link between the protective function of BAG3 and tau clearance in an excitatory neuron preferential manner.…”

Section: Bag3 In the Nervous Systemmentioning

confidence: 60%

The role of BAG3 in health and disease: A “Magic BAG of Tricks”

Lin

Koren

Cvetojevic

et al. 2021

J of Cellular Biochemistry

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The multi‐domain structure of Bcl‐2‐associated athanogene 3 (BAG3) facilitates its interaction with many different proteins that participate in regulating a variety of biological pathways. After revisiting the BAG3 literature published over the past ten years with Citespace software, we classified the BAG3 research into several clusters, including cancer, cardiomyopathy, neurodegeneration, and viral propagation. We then highlighted recent key findings in each cluster. To gain greater insight into the roles of BAG3, we analyzed five different published mass spectrometry data sets of proteins that co‐immunoprecipitate with BAG3. These data gave us insight into universal, as well as cell‐type‐specific BAG3 interactors in cancer cells, cardiomyocytes, and neurons. Finally, we mapped variable BAG3 SNPs and also mutation data from previous publications to further explore the link between the domains and function of BAG3. We believe this review will provide a better understanding of BAG3 and direct future studies towards understanding BAG3 function in physiological and pathological conditions.

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“…It plays an essential role in maintaining proteostasis and serves a protective role against neurodegeneration [14–16]. Previously, we demonstrated that BAG3 plays an important role in regulating MAPT clearance through autophagy [17,18], and, more recently, we found that BAG3 also regulates ESCRT-mediated MAPT clearance [19]. These findings point to the importance of BAG3 in both autophagy and ESCRT-mediated pathways.…”

Section: Introductionmentioning

confidence: 63%

“…Constructs: lentiviral vectors: shBAG3 (5’-AAGGTTCAGACCATCTTGGAA-3’), scrRNA (5’- CAGTCGCGTTTGCGACTGG-3’) in FG12 (with an H1 promoter) [21], or pHUUG with a U6 promoter (a generous gift of from Dr. C.Pröschel, University of Rochester) with and without GFP were used [19]. shSQSTM1 (5’- GAG GAA CTG ACA ATG GCC ATG TCC T −3’) was prepared in FG12, and shNBR1 (5’- GCA TGA CAG CCC TTT AAT AGA-3’) was prepared in pHUUG.…”

Section: Methodsmentioning

confidence: 99%

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BAG3 regulates the specificity of the recognition of specific MAPT species by NBR1 and SQSTM1

Lin

Sandkuhler

Dunlea

et al. 2023

Preprint

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Autophagy receptors are essential for the recognition and clearance of specific cargos by selective autophagy, which is essential for maintaining MAPT proteostasis. Previous studies have implicated different autophagy receptors in directing distinct species of MAPT to autophagy, but the underlying mechanisms have not been fully investigated. Here we examine how the autophagy receptors NBR1 and SQSTM1 differentially engage specific forms of MAPT and facilitate their clearance. In primary neurons depletion of NBR1, unlike depletion of SQSTM1, significantly increased phosphorylated MAPT levels. The specificity of the interactions were confirmed using in vitro binding assays with purified proteins. We provide direct evidence that NBR1 preferentially binds to monomeric MAPT, while SQSTM1 interacts predominantly with oligomeric MAPT, and that the co-chaperone BAG3 regulates the specificity of these interactions. Using an in vitro pulldown assay, we show that SQSTM1 only binds to monomeric MAPT when BAG3 is absent and fails to bind when BAG3 is present. The opposite is true of NBR1; its binding to monomeric MAPT was dependent on the presence of BAG3. Interestingly, in Alzheimer disease brain the association of NBR1 with BAG3 was significantly decreased. In a mouse model, ablation of BAG3 in neural cells disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT. Overall, our results uncover a novel role for BAG3 in regulating the specificity of selective autophagy receptors in targeting different species of MAPT and provide compelling evidence that BAG3 plays a key role in maintaining MAPT proteostasis.

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BAG3 Regulation of RAB35 Mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome Pathway and Tau Clearance

Cited by 17 publications

References 74 publications

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer’s disease

The role of BAG3 in health and disease: A “Magic BAG of Tricks”

BAG3 regulates the specificity of the recognition of specific MAPT species by NBR1 and SQSTM1

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