Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Kirk, Jonathan A.; Cheung, Joseph Y.; Feldman, Arthur M.

doi:10.1172/jci149415

Cited by 43 publications

(37 citation statements)

References 136 publications

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“…There are two major Protein Quality Control (PQC) systems in vertebrate cells, particularly in abundance in cardiomyocytes and skeletal muscle cells, that is, the Ubiquitin Proteasome System (UPS; Patel & Majetschak, 2007) and the BAG3 responsive autophagy pathway (Kirk, Cheung, & Feldman, 2021). BAG3 has been reported to play an important role in myofibril structure and stress related integrity (Homma et al, 2006; Knezevic et al, 2015), particularly via its binding to CapZ that binds to the barbed end of F‐actin filaments embedded in the Z‐Bands of mature myofibrils (Hishiya, Kitazawa, & Takayama, 2010; reviewed in Marzullo, Turco, & De Marco, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Wang et al (2007) reported that CapZ first appears in the nascent myofibrils in embryonic quail skeletal muscle myotubes. Some proteasome inhibitors (e.g., MG132, Bortezomib) have been reported to induce increased BAG3 expression (Kirk et al, 2021; Wang, Liu, Zhang, Guan, & Du, 2008). However, the proteasome inhibitor, calfilzomib, does not upregulate the level of BAG3 in treated cells (Dimopoulos et al, 2016; Kirk et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

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Inhibitors of the ubiquitin proteasome system block myofibril assembly in cardiomyocytes derived from chick embryos and human pluripotent stem cells

et al. 2021

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Details of sarcomeric protein assembly during de novo myofibril formation closely resemble myofibrillogenesis in skeletal and cardiac myocytes in birds, rodents, and zebrafish. The arrangement of proteins during myofibrillogenesis follows a three-step process: beginning with premyofibrils, followed by nascent myofibrils, and concluding with mature myofibrils (reviewed in Sanger et al., 2017). Assembly and maintenance of myofibrils in living muscle cells. In: Handbook of experimental pharmacology, 2017 [pp. 39-75]. Our aim is to determine if the same pathway is followed in human cardiomyocytes derived from human inducible pluripotent stem cells. We found that the human cardiomyocytes developed patterns of protein organization identical to the three-step series seen in the model organisms cited above. Further experiments showed that myofibril assembly can be blocked at the nascent myofibril by five different inhibitors of the Ubiquitin Proteasome System (UPS) stage in both avian and human cardiomyocytes. With the exception of Carfilzomib, removal of the UPS inhibitors allows nascent myofibrils to proceed to mature myofibrils. Some proteasomal inhibitors, such as Bortezomib and Carfilzomib, used to treat multiple myeloma patients, have off-target effects of damage to hearts in three to 6 % of these patients. These cardiovascular adverse events may result from prevention of mature myofibril formation in the cardiomyocytes. In summary, our results support a common three-step model for the formation of myofibrils ranging from avian to human cardiomyocytes. The Ubiquitin Proteasome System is required for progression from nascent myofibrils to mature myofibrils. Our experiments suggest a possible explanation for the cardiac and skeletal muscle off-target effects reported in multiple myeloma patients treated with proteasome inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Inhibitors of the ubiquitin proteasome system block myofibril assembly in cardiomyocytes derived from chick embryos and human pluripotent stem cells

et al. 2021

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“…Moreover, neural stem cell-derived EVs enhanced autophagy by increasing the expression of LC3 and Beclin1, confirming that the contents of EVs could play an important role in the autophagy process [ 47 ]. The co-chaperone BAG3 promotes autophagy and inhibits apoptosis by interacting with molecular chaperones and other anti-apoptotic proteins [ 48 ]. Published reports show that selective autophagy, including chaperone-assisted selective autophagy (CASA), plays a vital role in neuroinflammation [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles

et al. 2022

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Background The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death. Therefore, secretion of HSPB8 in OL-EVs could be beneficial for neurons during chronic inflammation. However, how secreted HSPB8 contribute to cellular proteostasis remains to be elucidated. Methods We produced oligodendroglia-derived EVs, either native (OL-EVs) or HSPB8 modified (OL-HSPB8-EVs), to investigate their effects in controlling chronic inflammation and cellular homeostasis. We analyzed the impact of both EV subsets on either a resting or activated microglial cell line and on primary mixed neural cell culture cells. Cells were activated by stimulating with either tumor necrosis factor-alpha and interleukin 1-beta or with phorbol-12-myristate-13-acetate. Results We show that OL-EVs and modified OL-HSPB8-EVs are internalized by C20 microglia and by primary mixed neural cells. The cellular uptake of OL-HSPB8-EVs increases the endogenous HSPB8 mRNA expression. Consistently, our results revealed that both EV subsets maintained cellular homeostasis during chronic inflammation with an increase in the formation of autophagic vesicles. Both EV subsets conveyed LC3B-II and BAG3 autophagy markers with an enhanced effect observed for OL-HSPB8-EVs. Moreover, stimulation with either native or modified OL-HSPB8-EVs showed a significant reduction in ubiquitinated protein, reactive oxygen species and mitochondrial depolarization, with OL-HSPB8-EVs exhibiting a more protective effect. Both EV subsets did not induce cell death in the C20 microglia cell line or the primary mixed neural cultures. Conclusion We demonstrate that the functions of oligodendroglia secreted EVs enriched with HSPB8 have a supportive role, comparable to the native OL-EVs. Further development of engineered oligodendroglia derived EVs could be a novel therapeutic strategy in countering chronic inflammation.

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“…61 Despite being a prominent therapeutic target for cancer and cardiomyopathy, the ubiquitous expression of BAG3 has posed the challenge of site-specific targeting of BAG3 regulation in the body. 62 Although targeted regulation of BAG3 expression by miRNAs could be highly effective against cancers, the delivery of miRNA in a specific manner is a well-known challenge. However, with the advent of new vehicles for miRNA delivery, the goal of using miRNAs as specific and effective therapeutic agent in multiple diseases, including those related to BAG3, seems to be attainable.…”

Section: Therapeutic Potential Of Mirnas Regulation Of Bag3 Expressionmentioning

confidence: 99%

MicroRNA regulation of BAG3

Singh

Dhanabalan

Verry

et al. 2022

Exp Biol Med (Maywood)

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B-cell lymphoma 2 (Bcl-2)-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that modulates major biological processes, including apoptosis, autophagy, and development to promote cellular adaptive responses to stress stimuli. Although BAG3 is constitutively expressed in several cell types, its expression is also inducible and is regulated by microRNAs (miRNAs). miRNAs are small non-coding RNAs that mostly bind to the 3′-UTR (untranslated region) of mRNAs to inhibit their translation or to promote their degradation. miRNAs can potentially regulate over 50% of the protein-coding genes in a cell and therefore are involved in the regulation of all major functions, including cell differentiation, growth, proliferation, apoptosis, and autophagy. Dysregulation of miRNA expression is associated with pathogenesis of numerous diseases, including peripheral artery disease (PAD). BAG3 plays a critical role in regulating the response of skeletal muscle cells to ischemia by its ability to regulate autophagy. However, the biological role of miRNAs in the regulation of BAG3 in biological processes has only been elucidated recently. In this review, we discuss how miRNA may play a key role in regulating BAG3 expression under normal and pathological conditions.

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Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Cited by 43 publications

References 136 publications

Inhibitors of the ubiquitin proteasome system block myofibril assembly in cardiomyocytes derived from chick embryos and human pluripotent stem cells

Inhibitors of the ubiquitin proteasome system block myofibril assembly in cardiomyocytes derived from chick embryos and human pluripotent stem cells

Oligodendroglia-derived extracellular vesicles activate autophagy via LC3B/BAG3 to protect against oxidative stress with an enhanced effect for HSPB8 enriched vesicles

MicroRNA regulation of BAG3

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