CEP55 promotes cilia disassembly through stabilizing Aurora A kinase

Abstract

Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55−/− mice display clinical manifestations of Meckel–Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55−/− mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel–Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.

Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis

“…Tedeschi et al [ 8 ] and our Cep55 knockout mice were generated using ES clones from the European mutant mice consortium, albeit using different clones (HEPD0726_6_A04; HEPD0726_6_B01). Both studies generated a tm1a allele, in C57BL/6 genetic background, but there could be substrain differences, whereas the other two studies generated mice using CRISPR-Cas9 in either a mixed C57BL/6 and FBV/N or pure C57BL/6 background [ 9 , 10 ]. These prior studies, also reported slight differences in postnatal lethality ranging from preweaning lethality with incomplete penetrance, ~7% homozygous mice viable between (P1- P14) to 100% mortality for KO pups at P2 [ 8 , 9 ].…”

“…Both studies generated a tm1a allele, in C57BL/6 genetic background, but there could be substrain differences, whereas the other two studies generated mice using CRISPR-Cas9 in either a mixed C57BL/6 and FBV/N or pure C57BL/6 background [ 9 , 10 ]. These prior studies, also reported slight differences in postnatal lethality ranging from preweaning lethality with incomplete penetrance, ~7% homozygous mice viable between (P1- P14) to 100% mortality for KO pups at P2 [ 8 , 9 ]. We observed a significant reduction in the numbers of KO pups obtained at P0 compared to the expected number based on Mendelian ratio.…”

“…This difference in P0 survival may be explained by genetic difference in substrain and different Cep55 ES tm1a clone used by us and Tedeschi et al [ 8 ]. Differences in the approach used to target Cep55 in the other two studies may also contribute to this discrepancy [ 9 , 10 ]. The different genetic backgrounds are known to have major effects on the penetrance and severity of phenotypes.…”

“…However, inhibition of activated Gsk3β, observed in Cep55 -/- MEFs and human organoids as a consequence of reduced Akt activation, could only rescue the phenotype through decreasing apoptosis without any impact on ciliogenesis, suggesting that other downstream effectors of Akt are involved in the regulation of ciliogenesis. Recently it was reported that Cep55 was required for cilia resorption [ 9 ]. The absence of cilia formation defect in this study may be a consequence of severity of Cep55 loss between mouse models.…”

Insights into the Regulation of Ciliary Disassembly

“…PLK1 has also been implicated in protein trafficking by phosphorylating the transition zone protein nephrocystin-1 [ 84 ]. Centrosomal protein of 55 kD (CEP55) is shown to facilitate the recruitment of chaperonin containing TCP1 chaperonin complex to AurA, stabilizing AurA and promoting ciliary disassembly [ 85 ]. Studies from our lab have shown that the centrosomal integrity/mitotic surveillance (CI) pathway comprising USP28, p53, and 53BP1 plays a significant role in cilia disassembly downstream of polycystin genes ( Pkd1 or Pkd2 ) [ 43 ].…”