TY - JOUR
T1 - MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes
AU - Yamada, Hiroyuki
AU - Shirata, Naritoshi
AU - Makino, Shinichi
AU - Miyake, Takafumi
AU - Trejo, Juan Alejandro Oliva
AU - Yamamoto-Nonaka, Kanae
AU - Kikyo, Mitsuhiro
AU - Empitu, Maulana A.
AU - Kadariswantiningsih, Ika N.
AU - Kimura, Maiko
AU - Ichimura, Koichiro
AU - Yokoi, Hideki
AU - Mukoyama, Masashi
AU - Hotta, Akitsu
AU - Nishimori, Katsuhiko
AU - Yanagita, Motoko
AU - Asanuma, Katsuhiko
N1 - Publisher Copyright:
© 2020 International Society of Nephrology
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - FSGS
KW - MAGI-2
KW - MAGI2
KW - neph1
KW - nephrin
KW - podocyte
UR - http://www.scopus.com/inward/record.url?scp=85099852971&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2020.09.027
DO - 10.1016/j.kint.2020.09.027
M3 - Article
C2 - 33144214
AN - SCOPUS:85099852971
SN - 0085-2538
VL - 99
SP - 382
EP - 395
JO - Kidney International
JF - Kidney International
IS - 2
ER -