MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes

Hiroyuki Yamada, Naritoshi Shirata, Shinichi Makino, Takafumi Miyake, Juan Alejandro Oliva Trejo, Kanae Yamamoto-Nonaka, Mitsuhiro Kikyo, Maulana A. Empitu, Ika N. Kadariswantiningsih, Maiko Kimura, Koichiro Ichimura, Hideki Yokoi, Masashi Mukoyama, Akitsu Hotta, Katsuhiko Nishimori, Motoko Yanagita, Katsuhiko Asanuma

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Podocytes are highly specialized cells within the glomerulus that are essential for ultrafiltration. The slit diaphragm between the foot processes of podocytes functions as a final filtration barrier to prevent serum protein leakage into urine. The slit-diaphragm consists mainly of Nephrin and Neph1, and localization of these backbone proteins is essential to maintaining the integrity of the glomerular filtration barrier. However, the mechanisms that regulate the localization of these backbone proteins have remained elusive. Here, we focused on the role of membrane-associated guanylate kinase inverted 2 (MAGI-2) in order to investigate mechanisms that orchestrate localization of slit-diaphragm backbone proteins. MAGI-2 downregulation coincided with a reduced expression of slit-diaphragm backbone proteins in human kidneys glomerular disease such as focal segmental glomerulosclerosis or IgA nephropathy. Podocyte-specific deficiency of MAGI-2 in mice abrogated localization of Nephrin and Neph1 independently of other scaffold proteins. Although a deficiency of zonula occuldens-1 downregulated the endogenous Neph1 expression, MAGI-2 recovered Neph1 expression at the cellular edge in cultured podocytes. Additionally, overexpression of MAGI-2 preserved Nephrin localization to intercellular junctions. Co-immunoprecipitation and pull-down assays also revealed the importance of the PDZ domains of MAGI-2 for the interaction between MAGI-2 and slit diaphragm backbone proteins in podocytes. Thus, localization and stabilization of Nephrin and Neph1 in intercellular junctions is regulated mainly via the PDZ domains of MAGI-2 together with other slit-diaphragm scaffold proteins. Hence, these findings may elucidate a mechanism by which the backbone proteins are maintained.

Original languageEnglish
Pages (from-to)382-395
Number of pages14
JournalKidney International
Volume99
Issue number2
DOIs
Publication statusPublished - Feb 2021
Externally publishedYes

Keywords

  • FSGS
  • MAGI-2
  • MAGI2
  • neph1
  • nephrin
  • podocyte

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