The establishment and maintenance of planar cell polarity (PCP) has an essential role in embryonic development and in normal tissue function. New findings from Zheng Dong and colleagues suggest that the PCP effector protein inturned (Intu) also protects against renal ischaemia–reperfusion injury (IRI) by promoting cell survival and ciliogenesis.
Several PCP effector proteins, including Intu, have roles in the regulation of ciliogenesis, so are classified as ciliogenesis and planar polarity effector proteins. “Previous work from our group and others has implicated primary cilia in kidney injury,” comments Dong. “However, the role of PCP proteins in kidney injury and repair is poorly understood.”
To investigate this role, the researchers generated mice with specific knockout of Intu in the proximal tubules. They report that renal IRI induced Intu expression in the kidneys of wild-type mice but not in those of the Intu knockouts. Following renal IRI, renal tubule damage and cell death were increased and post-injury ciliogenesis was reduced in the Intu-knockout mice compared with wild-type controls. “These findings provide the first compelling evidence for an involvement of PCP in the response to renal IRI,” says Dong.
Using tandem affinity purification in conjunction with mass spectrometry, the researchers identified signal transducer and activator of transcription 1 (STAT1) as a novel interacting partner of Intu. In proximal tubule cells, Intu and STAT1 colocalized at the centriole and basal body area. During cell stress, Intu expression suppressed STAT1 expression, reduced cell death and preserved cilia length, whereas Intu deficiency resulted in accumulation of STAT1 and increased cell death and ciliary defects. Knockdown of STAT1 attenuated these effects in Intu-silenced cells.
“Mechanistically, we have identified a novel interaction between Intu and STAT1,” says Dong. “Our findings suggest that by interacting with STAT1, Intu may promote STAT1 degradation via the proteasome, resulting in ciliogenesis and cell survival during cell stress. Together, these results indicate that Intu protects cells and tissues from injury by targeting STAT1 for degradation and maintaining primary cilia.”
Wang, S. et al. The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation. Nat. Commun. 9, 1234 (2018)
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Carney, E.F. Intu protects the kidney. Nat Rev Nephrol 14, 354 (2018). https://doi.org/10.1038/s41581-018-0010-x