Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier
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Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier. / Köhler, Sybille; Odenthal, Johanna; Ludwig, Vivian; Unnersjö-Jess, David; Höhne, Martin; Jüngst, Christian; Grawe, Ferdi; Helmstädter, Martin; Janku, Johanna L; Bergmann, Carsten; Hoyer, Peter F; Hagmann, Henning; Walz, Gerd; Bloch, Wilhelm; Niessen, Carien M.; Schermer, Bernhard; Wodarz, Andreas; Denholm, Barry; Benzing, Thomas; Iden, Sandra; Brinkkoetter, Paul Thomas.
in: KIDNEY INT, Jahrgang 101, Nr. 4, 04.2022, S. P733-751.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier
AU - Köhler, Sybille
AU - Odenthal, Johanna
AU - Ludwig, Vivian
AU - Unnersjö-Jess, David
AU - Höhne, Martin
AU - Jüngst, Christian
AU - Grawe, Ferdi
AU - Helmstädter, Martin
AU - Janku, Johanna L
AU - Bergmann, Carsten
AU - Hoyer, Peter F
AU - Hagmann, Henning
AU - Walz, Gerd
AU - Bloch, Wilhelm
AU - Niessen, Carien M.
AU - Schermer, Bernhard
AU - Wodarz, Andreas
AU - Denholm, Barry
AU - Benzing, Thomas
AU - Iden, Sandra
AU - Brinkkoetter, Paul Thomas
PY - 2022/4
Y1 - 2022/4
N2 - Glomerular diseases are a major cause for chronic kidney disorders. In most cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and loss of podocytes. Here, we establish a link between the Par3 polarity complex and actin regulators necessary to establish and maintain podocyte architecture by utilizing mouse and Drosophila models to characterize the functional role of Par3A and Par3B and its fly homologue Bazooka in vivo. Only simultaneous inactivation of both Par3 proteins caused a severe disease phenotype. Rescue experiments in Drosophila nephrocytes revealed atypical protein kinase C (aPKC)-Par6 dependent and independent effects. While Par3A primarily acts via aPKC-Par6, Par3B function was independent of Par6. Actin-associated synaptopodin protein levels were found to be significantly upregulated upon loss of Par3A/B in mouse podocytes. Tropomyosin2, which shares functional similarities with synaptopodin, was also elevated in Bazooka depleted nephrocytes. The simultaneous depletion of Bazooka and Tropomyosin2 resulted in a partial rescue of the Bazooka knockdown phenotype and prevented increased Rho1-GTP, a member of a GTPase protein family regulating the cytoskeleton. The latter contribute to the nephrocyte phenotype observed upon loss of Bazooka. Thus, we demonstrate that Par3 proteins share a high functional redundancy but also have specific functions. Par3A acts in an aPKC-Par6 dependent way and regulates RhoA-GTP levels, while Par3B exploits Par6 independent functions influencing synaptopodin localization. Hence, Par3A and Par3B link elements of polarity signaling and actin regulators to maintain podocyte architecture.
AB - Glomerular diseases are a major cause for chronic kidney disorders. In most cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and loss of podocytes. Here, we establish a link between the Par3 polarity complex and actin regulators necessary to establish and maintain podocyte architecture by utilizing mouse and Drosophila models to characterize the functional role of Par3A and Par3B and its fly homologue Bazooka in vivo. Only simultaneous inactivation of both Par3 proteins caused a severe disease phenotype. Rescue experiments in Drosophila nephrocytes revealed atypical protein kinase C (aPKC)-Par6 dependent and independent effects. While Par3A primarily acts via aPKC-Par6, Par3B function was independent of Par6. Actin-associated synaptopodin protein levels were found to be significantly upregulated upon loss of Par3A/B in mouse podocytes. Tropomyosin2, which shares functional similarities with synaptopodin, was also elevated in Bazooka depleted nephrocytes. The simultaneous depletion of Bazooka and Tropomyosin2 resulted in a partial rescue of the Bazooka knockdown phenotype and prevented increased Rho1-GTP, a member of a GTPase protein family regulating the cytoskeleton. The latter contribute to the nephrocyte phenotype observed upon loss of Bazooka. Thus, we demonstrate that Par3 proteins share a high functional redundancy but also have specific functions. Par3A acts in an aPKC-Par6 dependent way and regulates RhoA-GTP levels, while Par3B exploits Par6 independent functions influencing synaptopodin localization. Hence, Par3A and Par3B link elements of polarity signaling and actin regulators to maintain podocyte architecture.
U2 - 10.1016/j.kint.2021.11.030
DO - 10.1016/j.kint.2021.11.030
M3 - SCORING: Journal article
VL - 101
SP - P733-751
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 4
ER -