Expression of the Murine αB-Crystallin Gene in Lens and Skeletal Muscle: Identification of a Muscle-Preferred Enhancer

Dubin, Robert; Gopal-Srivastava, Rashmi; Wawrousek, Eric F.; Piatigorsky, Joram

doi:10.1128/mcb.11.9.4340-4349.1991

Cited by 21 publications

(1 citation statement)

References 51 publications

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“…αB-crystallin is ubiquitously expressed or stress-induced in most tissues and cells, including heart, skeletal muscle, kidney, lung, brain, and retina. αA-crystallin, however, is basally expressed at low levels in a limited number of tissues while highly induced under stress conditions in the kidney and the central nervous system, including the retina ( Dubin et al, 1991 ; Zhang et al, 2019 ). In the retina, both α-crystallin proteins have been found predominantly in glia and retinal ganglion cells (RGCs) in the inner retina, as well as photoreceptors and retinal pigmental epithelium (RPE) in the outer retina ( Rao et al, 2008 ; Munemasa et al, 2009 ; Kase et al, 2012 ; Shi et al, 2015 ; Kannan et al, 2016 ; Ruebsam et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Evidence for Paracrine Protective Role of Exogenous αA-Crystallin in Retinal Ganglion Cells

Nath

Sluzala

Phadte

et al. 2022

eNeuro

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Expression and secretion of neurotrophic factors have long been known as a key mechanism of neuroglial interaction in the central nervous system. In addition, several other intrinsic neuroprotective pathways have been described, including those involving small heat shock proteins such as α-crystallins. While initially considered as a purely intracellular mechanism, both αA-crystallins and αB-crystallins have been recently reported to be secreted by glial cells. While an anti-apoptotic effect of such secreted αA-crystallin has been suggested, its regulation and protective potential remain unclear. We recently identified residue threonine 148 (T148) and its phosphorylation as a critical regulator of αA-crystallin intrinsic neuroprotective function. In the current study, we explored how mutation of this residue affected αA-crystallin chaperone function, secretion, and paracrine protective function using primary glial and neuronal cells. After demonstrating the paracrine protective effect of αA-crystallins secreted by primary Müller glial cells (MGCs), we purified and characterized recombinant αA-crystallin proteins mutated on the T148 regulatory residue. Characterization of the biochemical properties of these mutants revealed an increased chaperone activity of the phosphomimetic T148D mutant. Consistent with this observation, we also show that exogeneous supplementation of the phosphomimetic T148D mutant protein protected primary retinal neurons from metabolic stress despite similar cellular uptake. In contrast, the nonphosphorylatable mutant was completely ineffective. Altogether, our study demonstrates the paracrine role of αA-crystallin in the central nervous system as well as the therapeutic potential of functionally enhanced αA-crystallin recombinant proteins to prevent metabolic-stress induced neurodegeneration.

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Section: Introductionmentioning

confidence: 99%

Evidence for Paracrine Protective Role of Exogenous αA-Crystallin in Retinal Ganglion Cells

Nath

Sluzala

Phadte

et al. 2022

eNeuro

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Toward a Molecular Basis of Alcohol Use and Abuse

Jansson¹,

Jörnvall²,

Rydberg³

et al. 1994

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Sequence and Functional Conservation of the Intergenic Region Between the Head-to-Head Genes Encoding the Small Heat Shock Proteins αB-Crystallin and HspB2 in the Mammalian Lineage

et al. 2004

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An unexpected feature of the large mammalian genome is the frequent occurrence of closely linked head-to-head gene pairs. Close apposition of such gene pairs has been suggested to be due to sharing of regulatory elements. We show here that the head-to-head gene pair encoding two small heat shock proteins, alphaB-crystallin and HspB2, is closely linked in all major mammalian clades, suggesting that this close linkage is of selective advantage. Yet alphaB-crystallin is abundantly expressed in lens and muscle and in response to a heat shock, while HspB2 is abundant only in muscle and not upregulated by a heat shock. The intergenic distance between the genes for these two proteins in mammals ranges from 645 bp (platypus) to 1069 bp (opossum), with an average of about 900 bp; in chicken the distance was the same as in duck (1.6 kb). Phylogenetic footprinting and sequence alignment identified a number of conserved sequence elements close to the HspB2 promoter and two farther upstream. All known regulatory elements of the mouse alphaB-crystallin promoter are conserved, except in platypus and birds. The lens-specific region 1 (LSR1) and the heat shock elements (HSEs) lack in birds; in platypus the LSR1 is reduced to a Pax-6 site, while the Pax-6 site in LSR2 and a HSE are absent. Most likely the primordial mammalian alphaB-crystallin promoter had two LSRs and two HSEs. In transfection experiments the platypus alphaB-crystallin promoter retained heat shock responsiveness and lens expression. It also directed lens expression in Xenopus laevis transgenes, as did the HspB2 promoter of rat or blind mole rat. Deletion of the middle of the intergenic region including the upstream enhancer affected the activity of both the rat alphaB-crystallin and the HspB2 promoters, suggesting sharing of the enhancer region by the two promoters.

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Expression of the Murine αB-Crystallin Gene in Lens and Skeletal Muscle: Identification of a Muscle-Preferred Enhancer

Cited by 21 publications

References 51 publications

Evidence for Paracrine Protective Role of Exogenous αA-Crystallin in Retinal Ganglion Cells

Evidence for Paracrine Protective Role of Exogenous αA-Crystallin in Retinal Ganglion Cells

Toward a Molecular Basis of Alcohol Use and Abuse

Sequence and Functional Conservation of the Intergenic Region Between the Head-to-Head Genes Encoding the Small Heat Shock Proteins αB-Crystallin and HspB2 in the Mammalian Lineage

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