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Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+ homeostasis proteins.

Tuvia S, Buhusi M, Davis L, Reedy M, Bennett V - J. Cell Biol. (1999)

Bottom Line: Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle.These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins.Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca(2+) homeostasis compartment of the ER.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Departments of Cell Biology and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
This report describes a congenital myopathy and major loss of thymic lymphocytes in ankyrin-B (-/-) mice as well as dramatic alterations in intracellular localization of key components of the Ca(2+) homeostasis machinery in ankyrin-B (-/-) striated muscle and thymus. The sarcoplasmic reticulum (SR) and SR/T-tubule junctions are apparently preserved in a normal distribution in ankyrin-B (-/-) skeletal muscle based on electron microscopy and the presence of a normal pattern of triadin and dihydropyridine receptor. Therefore, the abnormal localization of SR/ER Ca ATPase (SERCA) and ryanodine receptors represents a defect in intracellular sorting of these proteins in skeletal muscle. Extrapolation of these observations suggests defective targeting as the basis for abnormal localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3 receptors in the thymus of ankyrin-B (-/-) mice. Mis-sorting of SERCA 2 and ryanodine receptor 2 in ankyrin-B (-/-) cardiomyocytes is rescued by expression of 220-kD ankyrin-B, demonstrating that lack of the 220-kD ankyrin-B polypeptide is the primary defect in these cells. Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle. These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins. Ankyrin-B is a member of a family of adapter proteins implicated in restriction of diverse proteins to specialized plasma membrane domains. Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca(2+) homeostasis compartment of the ER.

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Toluidine blue–stained plastic sections of day 1 thymus from ankyrin-B (+/+) and (−/−) mice. Top panels are located at the cortex. An asterisk marks the margin of the thymus. Higher magnification images are shown at the bottom. Note that most of the nuclei of ankyrin-B (−/−) lymphocytes are condensed and pyknotic. Bars: (top) 25 μm; (bottom) 10 μm.
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Figure 11: Toluidine blue–stained plastic sections of day 1 thymus from ankyrin-B (+/+) and (−/−) mice. Top panels are located at the cortex. An asterisk marks the margin of the thymus. Higher magnification images are shown at the bottom. Note that most of the nuclei of ankyrin-B (−/−) lymphocytes are condensed and pyknotic. Bars: (top) 25 μm; (bottom) 10 μm.

Mentions: Reduced accumulation and abnormal localization of IP3 receptors in ankyrin-B (−/−) thymus would be anticipated to interrupt normal calcium signaling and differentiation of T cells. Consistent with such a loss of signaling, Toluidine blue–stained sections of ankyrin-B (−/−) neonatal thymus reveal cell death of a major fraction of T cells (Fig. 11). Epithelial cells are present in equivalent numbers and organization, while the majority of T cells are missing or exhibit pyknotic nuclei. In contrast, sections of normal thymus are densely populated with T cells containing normal nuclei.


Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+ homeostasis proteins.

Tuvia S, Buhusi M, Davis L, Reedy M, Bennett V - J. Cell Biol. (1999)

Toluidine blue–stained plastic sections of day 1 thymus from ankyrin-B (+/+) and (−/−) mice. Top panels are located at the cortex. An asterisk marks the margin of the thymus. Higher magnification images are shown at the bottom. Note that most of the nuclei of ankyrin-B (−/−) lymphocytes are condensed and pyknotic. Bars: (top) 25 μm; (bottom) 10 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2169334&req=5

Figure 11: Toluidine blue–stained plastic sections of day 1 thymus from ankyrin-B (+/+) and (−/−) mice. Top panels are located at the cortex. An asterisk marks the margin of the thymus. Higher magnification images are shown at the bottom. Note that most of the nuclei of ankyrin-B (−/−) lymphocytes are condensed and pyknotic. Bars: (top) 25 μm; (bottom) 10 μm.
Mentions: Reduced accumulation and abnormal localization of IP3 receptors in ankyrin-B (−/−) thymus would be anticipated to interrupt normal calcium signaling and differentiation of T cells. Consistent with such a loss of signaling, Toluidine blue–stained sections of ankyrin-B (−/−) neonatal thymus reveal cell death of a major fraction of T cells (Fig. 11). Epithelial cells are present in equivalent numbers and organization, while the majority of T cells are missing or exhibit pyknotic nuclei. In contrast, sections of normal thymus are densely populated with T cells containing normal nuclei.

Bottom Line: Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle.These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins.Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca(2+) homeostasis compartment of the ER.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute and Departments of Cell Biology and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.

ABSTRACT
This report describes a congenital myopathy and major loss of thymic lymphocytes in ankyrin-B (-/-) mice as well as dramatic alterations in intracellular localization of key components of the Ca(2+) homeostasis machinery in ankyrin-B (-/-) striated muscle and thymus. The sarcoplasmic reticulum (SR) and SR/T-tubule junctions are apparently preserved in a normal distribution in ankyrin-B (-/-) skeletal muscle based on electron microscopy and the presence of a normal pattern of triadin and dihydropyridine receptor. Therefore, the abnormal localization of SR/ER Ca ATPase (SERCA) and ryanodine receptors represents a defect in intracellular sorting of these proteins in skeletal muscle. Extrapolation of these observations suggests defective targeting as the basis for abnormal localization of ryanodine receptors, IP3 receptors and SERCA in heart, and of IP3 receptors in the thymus of ankyrin-B (-/-) mice. Mis-sorting of SERCA 2 and ryanodine receptor 2 in ankyrin-B (-/-) cardiomyocytes is rescued by expression of 220-kD ankyrin-B, demonstrating that lack of the 220-kD ankyrin-B polypeptide is the primary defect in these cells. Ankyrin-B is associated with intracellular vesicles, but is not colocalized with the bulk of SERCA 1 or ryanodine receptor type 1 in skeletal muscle. These data provide the first evidence of a physiological requirement for ankyrin-B in intracellular targeting of the calcium homeostasis machinery of striated muscle and immune system, and moreover, support a catalytic role that does not involve permanent stoichiometric complexes between ankyrin-B and targeted proteins. Ankyrin-B is a member of a family of adapter proteins implicated in restriction of diverse proteins to specialized plasma membrane domains. Similar mechanisms involving ankyrins may be essential for segregation of functionally defined proteins within specialized regions of the plasma membrane and within the Ca(2+) homeostasis compartment of the ER.

Show MeSH
Related in: MedlinePlus