HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis

Kennedy, Donna; Mnich, Katarzyna; Oommen, Deepu; Chakravarthy, Reka; Almeida-Souza, Le­onardo; Krols, Michiel; Saveljeva, Svetlana; Doyle, Karen M.; Gupta, Sanjeev; Timmerman, Vincent; Janssens, Sophie; Gorman, Adrienne M.; Samali, Afshin

doi:10.1038/cddis.2017.408

Cited by 41 publications

(29 citation statements)

References 58 publications

(82 reference statements)

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“…As mutating the Cys137 residue abolishes the protective function, it may act as a redox sensor or directly react with oxidative species [305,308]. HSPB1 has also been described a potent anti-apoptotic molecule: it suppresses apoptosis by regulating both the intrinsic and Fas-induced apoptosis pathways at several stages [220,309,[315][316][317][318][319][320][321][322].…”

Section: Hspb1mentioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

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Section: Hspb1mentioning

confidence: 99%

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Sarparanta

Jonson

Kawan

et al. 2020

IJMS

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“…Recently, ERK1/2 interaction with heat shock protein B1 (HSPB1) was shown to facilitate the phosphorylation of the BH3‐only protein Bim leading to its degradation and ultimately impairing ER stress‐induced apoptosis . Intriguingly, HSPB1 mutations from Charcot‐Marie‐Tooth disease exhibit high levels of BIM and are more vulnerable to ER stress‐induced cell death than their wild‐type counterparts . However, ERK1/2 phosphorylation of Bcl‐2 and Mcl‐1 has been described to have conflicting effects in the literature .…”

Section: Mitogen‐activated Protein Kinases (Mapks)mentioning

confidence: 99%

“…65 Intriguingly, HSPB1 mutations from Charcot-Marie-Tooth disease exhibit high levels of BIM and are more vulnerable to ER stress-induced cell death than their wild-type counterparts. 65 However, ERK1/2 phosphorylation of Bcl-2 and Mcl-1 has been described to have conflicting effects in the literature. 66 For example, ERK1/2 phosphorylation of Bcl-2 can prevent Bcl-2 function activating neuronal apoptosis [67][68][69][70] ; meanwhile, other reports indicate that ERK1/2 phosphorylation of Bcl-2 promotes the protein's anti-apoptotic activities.…”

Section: Extracellular Regulated Kinasementioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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“…In addition to regulations at the level of gene expression, further studies revealed that posttranslational modifications such as Ser/Thr phosphorylation of prosurvival proteins is also vital for thymocyte survival. For example, phosphorylation of different sites in Mcl-1 play opposing roles in thymocyte survival, while changes in Ser/Thr phosphorylation status of the proapoptotic protein Bim have also been implicated in the decision of cell survival or cell death during negative selection (7,8). ERK activation, which is also marked by Ser/Thr phosphorylation, has been shown to be essential for the positive selection of thymocytes (9).…”

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confidence: 99%

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

Zheng

Zhao

et al. 2019

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

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The development of thymocytes to mature T cells in the thymus is tightly controlled by cellular selection, in which only a small fraction of thymocytes equipped with proper quality of TCRs progress to maturation. It is pivotal to protect the survival of the few T cells, which pass the selection. However, the signaling events, which safeguard the cell survival in thymus, are not totally understood. In this study, protein Ser/Thr phosphorylation in thymocytes undergoing positive selection is profiled by mass spectrometry. The results revealed large numbers of dephosphorylation changes upon T cell receptor (TCR) activation during positive selection. Subsequent substrate analysis pinpointed protein phosphatase 2A (PP2A) as the enzyme responsible for the dephosphorylation changes in developing thymocytes. PP2A catalytic subunit α (Ppp2ca) deletion in the T cell lineage in Ppp2ca flox/flox -Lck-Cre mice (PP2A cKO) displayed dysregulated dephosphorylation of apoptosis-related proteins in double-positive (DP) cells and caused substantially decreased numbers of DP CD4 + CD8 + cells. Increased levels of apoptosis in PP2A cKO DP cells were found to underlie aberrant thymocyte development. Finally, the defective thymocyte development in PP2A cKO mice could be rescued by either Bcl2 transgene expression or by p53 knockout. In summary, our work reveals an essential role of PP2A in promoting thymocyte development through the regulation of cell survival. thymocyte selection | PP2A | apoptosis T lymphocytes are the major form of adaptive immune cells that target pathogens (1, 2). T cell precursors originate in the bone marrow and then migrate to the thymus to initiate differentiation into mature T cells. In the thymus, CD4 -CD8doublenegative (DN) thymocytes (which can be subcategorized as stages DN1-DN4) acquire T cell receptor (TCR) expression through VDJ recombination and develop into CD4 + CD8 + double-positive (DP) thymocytes, which subsequently give rise to CD4 + or CD8 + single-positive (SP) T cells. Two pivotal selection processes occur, namely positive selection and negative selection, and both serve as gatekeepers in the progress of DP T cells to the SP stage. Notably, only a small percentage of DP thymocytes survive through the selection process to become mature T cells bearing TCRs with suitable reactivity. Secure survival of the T cells which do pass selection is then of pivotal importance during thymic development.It has been shown that TCRs on the DP cell surface can bind to self-peptide-major histocompatibility complex (MHC) complexes on thymic epithelial and dendritic cells, which provide signals for thymocyte survival (3-5). Up-regulation of expression of survival-related proteins is one of the known mechanisms to promote thymocyte survival in this context. Well-studied examples include the Bcl-2 family prosurvival proteins Bcl-xL, whose stage-specific enrichment promotes the survival of DP thymocytes (6). In addition to regulations at the level of gene expression, further studies revealed that posttranslational ...

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HSPB1 facilitates ERK-mediated phosphorylation and degradation of BIM to attenuate endoplasmic reticulum stress-induced apoptosis

Cited by 41 publications

References 58 publications

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Protein phosphatase 2A has an essential role in promoting thymocyte survival during selection

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