Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat

J. Samuel Zigler, Cheng Zhang, Rhonda Grebe, Gitanjali Sehrawat, Laszlo Hackler, Souvonik Adhya, Stacey Hose, D. Scott McLeod, Imran Bhutto, Walid Barbour, Geetha Parthasarathy, Donald J. Zack, Yuri Sergeev, Gerard A. Lutty, James T. Handa, Debasish Sinha

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that βA3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the βA3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, βA3/A1-crystallin is localized to the lysosomes. However, in the Nuc1 RPE, βA3/A1-crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. βA3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material.

Original languageEnglish (US)
Pages (from-to)523-531
Number of pages9
JournalJournal of Cell Science
Volume124
Issue number4
DOIs
StatePublished - Feb 15 2011
Externally publishedYes

Fingerprint

Phagosomes
Crystallins
Epithelium
Mutation
Genes
Phagocytosis
Autophagy
Lysosomes
4 alpha-glucanotransferase
Cathepsin D
Crystalline Lens
Mutant Proteins
Masks
Protein Sorting Signals
Proteolysis
Digestion
Proteins
Enzymes

Keywords

  • βA3/A1-crystallin
  • Autophagy
  • Cathepsin D
  • Lysosome
  • Phagocytosis
  • Photoreceptor outer segment discs
  • Retinal pigmented epithelium (RPE)

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat. / Samuel Zigler, J.; Zhang, Cheng; Grebe, Rhonda; Sehrawat, Gitanjali; Hackler, Laszlo; Adhya, Souvonik; Hose, Stacey; McLeod, D. Scott; Bhutto, Imran; Barbour, Walid; Parthasarathy, Geetha; Zack, Donald J.; Sergeev, Yuri; Lutty, Gerard A.; Handa, James T.; Sinha, Debasish.

In: Journal of Cell Science, Vol. 124, No. 4, 15.02.2011, p. 523-531.

Research output: Contribution to journalArticle

Samuel Zigler, J, Zhang, C, Grebe, R, Sehrawat, G, Hackler, L, Adhya, S, Hose, S, McLeod, DS, Bhutto, I, Barbour, W, Parthasarathy, G, Zack, DJ, Sergeev, Y, Lutty, GA, Handa, JT & Sinha, D 2011, 'Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat', Journal of Cell Science, vol. 124, no. 4, pp. 523-531. https://doi.org/10.1242/jcs.078790
Samuel Zigler, J. ; Zhang, Cheng ; Grebe, Rhonda ; Sehrawat, Gitanjali ; Hackler, Laszlo ; Adhya, Souvonik ; Hose, Stacey ; McLeod, D. Scott ; Bhutto, Imran ; Barbour, Walid ; Parthasarathy, Geetha ; Zack, Donald J. ; Sergeev, Yuri ; Lutty, Gerard A. ; Handa, James T. ; Sinha, Debasish. / Mutation in the βA3/A1-crystallin gene impairs phagosome degradation in the retinal pigmented epithelium of the rat. In: Journal of Cell Science. 2011 ; Vol. 124, No. 4. pp. 523-531.
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AU - Hackler, Laszlo

AU - Adhya, Souvonik

AU - Hose, Stacey

AU - McLeod, D. Scott

AU - Bhutto, Imran

AU - Barbour, Walid

AU - Parthasarathy, Geetha

AU - Zack, Donald J.

AU - Sergeev, Yuri

AU - Lutty, Gerard A.

AU - Handa, James T.

AU - Sinha, Debasish

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N2 - Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that βA3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the βA3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, βA3/A1-crystallin is localized to the lysosomes. However, in the Nuc1 RPE, βA3/A1-crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. βA3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material.

AB - Phagocytosis of the shed outer segment discs of photoreceptors is a major function of the retinal pigmented epithelium (RPE). We demonstrate for the first time that βA3/A1-crystallin, a major structural protein of the ocular lens, is expressed in RPE cells. Further, by utilizing the Nuc1 rat, in which the βA3/A1-crystallin gene is mutated, we show that this protein is required by RPE cells for proper degradation of outer segment discs that have been internalized in phagosomes. We also demonstrate that in wild-type RPE, βA3/A1-crystallin is localized to the lysosomes. However, in the Nuc1 RPE, βA3/A1-crystallin fails to translocate to the lysosomes, perhaps because misfolding of the mutant protein masks sorting signals required for proper trafficking. The digestion of phagocytized outer segments requires a high level of lysosomal enzyme activity, and cathepsin D, the major enzyme responsible for proteolysis of the outer segments, is decreased in mutant RPE cells. Interestingly, our results also indicate a defect in the autophagy process in the Nuc1 RPE, which is probably also linked to impaired lysosomal function, because phagocytosis and autophagy might share common mechanisms in degradation of their targets. βA3/A1-crystallin is a novel lysosomal protein in RPE, essential for degradation of phagocytosed material.

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