Phosphorylation of αB-crystallin: Role in stress, aging and patho-physiological conditions

Raman, Bakthisaran; Akula, Kranthi Kiran; Tangirala, Ramakrishna; Rao, Ch. Mohan

doi:10.1016/j.bbagen.2015.09.017

Cited by 58 publications

(55 citation statements)

References 176 publications

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“…In inflammatory spinal cord lesions, stellate astrocytes express HSPB5 ser59 prominently, while hypertrophic astrocytes express HSPB5 ser19 and, to a lesser extent, HSPB5 ser45. HSPB5 is involved in a multitude of cellular processes by interacting with more than 90 different proteins, necessitating mechanisms to post‐translationally regulate HSPB5 activity, such as phosphorylation . HSPB5 can be phosphorylated at three different serine residues (ser19, ser45 and ser59).…”

Section: Discussionmentioning

confidence: 99%

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

Gorter¹,

Nutma²,

Jahrei³

et al. 2018

Clinical and Experimental Immunology

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SummaryMultiple sclerosis (MS) is a chronic neurodegenerative disease characterized by demyelination, inflammation and neurodegeneration throughout the central nervous system. Although spinal cord pathology is an important factor contributing to disease progression, few studies have examined MS lesions in the spinal cord and how they differ from brain lesions. In this study we have compared brain and spinal cord white (WM) and grey (GM) matter from MS and control tissues, focusing on small heat shock proteins (HSPB) and HSP16.2. Western blotting was used to examine protein levels of HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 in brain and spinal cord from MS and age‐matched non‐neurological controls. Immunohistochemistry was used to examine expression of the HSPs in MS spinal cord lesions and controls. Expression levels were quantified using ImageJ. Western blotting revealed significantly higher levels of HSPB1, HSPB6 and HSPB8 in MS and control spinal cord compared to brain tissues. No differences in HSPB5 and HSP16.2 protein levels were observed, although HSPB5 protein levels were higher in brain WM versus GM. In MS spinal cord lesions, increased HSPB1 and HSPB5 expression was observed in astrocytes, and increased neuronal expression of HSP16.2 was observed in normal‐appearing GM and type 1 GM lesions. The high constitutive expression of several HSPBs in spinal cord and increased expression of HSPBs and HSP16.2 in MS illustrate differences between brain and spinal cord in health and upon demyelination. Regional differences in HSP expression may reflect differences in astrocyte cytoskeleton composition and influence inflammation, possibly affecting the effectiveness of pharmacological agents.

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Section: Discussionmentioning

confidence: 99%

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

Gorter¹,

Nutma²,

Jahrei³

et al. 2018

Clinical and Experimental Immunology

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“…The second actor, αB‐crystallin, is known to be the molecular chaperone of desmin, playing a role in the localization and aggregation of desmin filaments as well as in its assembly . Activity of αB‐crystallin was first known to be regulated by phosphorylation, while its O‐GlcNAcylation on Thr170 seemed regulate its localization . Recently, the Thr162 residue on αB‐crystallin was identified to be O‐GlcNAcylated as well; this residue is located on its C‐terminal domain known to directly interact with desmin .…”

Section: Emergence Of a New Role Of O‐glcnacylation In The Sarcomere mentioning

confidence: 99%

O‐GlcNAcylation as a regulator of the functional and structural properties of the sarcomere in skeletal muscle: An update review

et al. 2019

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Although the O-GlcNAcylation process was discovered in 1984, its potential role in the physiology and physiopathology of skeletal muscle only emerged 20 years later. An increasing number of publications strongly support a key role of O-GlcNAcylation in the modulation of important cellular processes which are essential for skeletal muscle functions. Indeed, over a thousand of O-GlcNAcylated proteins have been identified within skeletal muscle since 2004, which belong to various classes of proteins, including sarcomeric proteins. In this review, we focused on these myofibrillar proteins, including contractile and structural proteins. Because of the modification of motor and regulatory proteins, the regulatory myosin light chain (MLC2) is related to several reports that support a key role of O-GlcNAcylation in the fine modulation of calcium activation parameters of skeletal muscle fibres, depending on muscle phenotype and muscle work. In addition, another key function of O-GlcNAcylation has recently emerged in the regulation of organization and reorganization of the sarcomere.Altogether, this data support a key role of O-GlcNAcylation in the homeostasis of sarcomeric cytoskeleton, known to be disturbed in many related muscle disorders.

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“…αB-crystallin is a molecular chaperone involved in the cell response to stress in various tissues (see reviews in [51,52]). Loss-of-function studies demonstrated that αB-crystallin is critical in maintaining lens proteostasis [37], and several missense mutations in human αB-crystallin gene are linked to hereditary cataracts, including P20S [53] and D140N [54].…”

Section: Expression Of Murine αB-crystallin R120g Mutant Induces Zebrmentioning

confidence: 99%

Transgenic Zebrafish Models Reveal Distinct Molecular Mechanisms for Cataract-linked αA-Crystallin Mutants

Zou

Mishra

et al. 2018

Preprint

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Mutations in the small heat shock proteins a-crystallins have been linked to autosomal dominant cataracts in humans. Extensive studies in vitro have revealed a spectrum of alterations to the structure and function of these proteins including shifts in the size of the oligomer, modulation of subunit exchange and modification of their affinity to client proteins. Although mouse models of these mutants were instrumental in identifying changes in cellular proliferation and lens development, a direct comparative analysis of their effects on lens proteostasis has not been performed. Here, we have transgenically expressed cataract-linked mutants of aAand aBcrystallin in the zebrafish lens to dissect the underlying molecular changes that contribute to the loss of lens optical properties. Zebrafish lines expressing these mutants displayed a range of morphological lens defects. Phenotype penetrance and severity were dependent on the mutation even in fish lines lacking endogenous a-crystallin. The mechanistic origins of these differences were investigated by the transgenic co-expression of a destabilized human gDcrystallin mutant. We found that the R49C but not the R116C mutant of aA-crystallin promoted aggregation of gD-crystallin, although both mutants have similar affinity to client proteins in vitro. Our working model attributes these differences to the propensity of R49C, located in the buried N-terminal domain of aA-crystallin, to disulfide crosslinking as previously demonstrated in vitro. Our findings complement and extend previous work in mouse models and emphasize the need of investigating chaperone/client protein interactions in appropriate cellular context.

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Phosphorylation of αB-crystallin: Role in stress, aging and patho-physiological conditions

Cited by 58 publications

References 176 publications

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

O‐GlcNAcylation as a regulator of the functional and structural properties of the sarcomere in skeletal muscle: An update review

Transgenic Zebrafish Models Reveal Distinct Molecular Mechanisms for Cataract-linked αA-Crystallin Mutants

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