Human SFI1 and Centrin form a complex critical for centriole architecture and ciliogenesis

Abstract

Over the course of evolution, the centrosome function has been conserved in most eukaryotes, but its core architecture has evolved differently in some clades, with the presence of centrioles in humans and a spindle pole body (SPB) in yeast. Similarly, the composition of these two core elements has diverged, with the exception of Centrin and SFI1, which form a complex in yeast to initiate SPB duplication. However, it remains unclear whether this complex exists at centrioles and whether its function has been conserved. Here, using expansion microscopy, we demonstrate that human SFI1 is a centriolar protein that associates with a pool of Centrin at the distal end of the centriole. We also find that both proteins are recruited early during procentriole assembly and that depletion of SFI1 results in the loss of the distal pool of Centrin, without altering centriole duplication. Instead, we show that SFI1/Centrin complex is essential for centriolar architecture, CEP164 distribution, and CP110 removal during ciliogenesis. Together, our work reveals a conserved SFI1/Centrin module displaying divergent functions between mammals and yeast.

CCDC15 localizes to the centriole inner scaffold and regulates centriole integrity and ciliogenesis

“…As previously described, POC5 depletion did not alter percentage of cells with distal SFI1 centriolar pools (Fig. 6D, E) (Laporte et al, 2022). These results identify CCDC15 as a dual regulator of centriolar recruitment of inner scaffold protein POC1B and the distal end SFI1/Centrin complex.…”

“…Previous studies showed that the inner scaffold proteins including WDR90, Centrin-2 and POC5, as well as the distal SFI1/Centrin complex are required for proper cilium formation and function (Delaval et al, 2011; Hassan et al, 2019; Laporte et al, 2022; Prosser and Morrison, 2015; Steib et al, 2020). To investigate whether CCDC15 functions in cilium assembly, we depleted CCDC15 in RPE1 cells and quantified the percentage of ciliated cells upon 48-h serum starvation.…”

“…The distal end of the centrioles is directly engaged in ciliogenesis via removal of the CP110/CEP97 centriole cap complex and recruitment of ciliogenesis factors (Kim and Dynlacht, 2013; Sanchez and Dynlacht, 2016). For example, the inner scaffold protein Centrin-2 also localizes to the centriole distal end where it interacts with SFI1 and regulates centriole architecture as well as ciliogenesis by removing the CP110 cap (Laporte et al, 2022). Unlike Centrin-2, CCDC15 localization was limited to the central core of the centrioles, which is reminiscent of most of the known inner scaffold proteins (Hamel et al, 2017; Laporte et al, 2022; Le Guennec et al, 2020; Steib et al, 2020).…”

“…For example, the inner scaffold protein Centrin-2 also localizes to the centriole distal end where it interacts with SFI1 and regulates centriole architecture as well as ciliogenesis by removing the CP110 cap (Laporte et al, 2022). Unlike Centrin-2, CCDC15 localization was limited to the central core of the centrioles, which is reminiscent of most of the known inner scaffold proteins (Hamel et al, 2017; Laporte et al, 2022; Le Guennec et al, 2020; Steib et al, 2020). Despite its central core localization, depletion of CCDC15 resulted in the loss of the distal pool of Centrin-2 without altering its localization to the central core.…”

Case report: NUT carcinoma with MXI1::NUTM1 fusion characterized by abdominopelvic lesions and ovarian masses in a middle-aged female

“…It has been found to be related to inflammatory bowel disease ( 18 ), X-linked myotubular myopathy ( 17 , 19 ), and type 4B Charcot-Marie-Tooth disease ( 20 ). SFI1 (SFI1 Centrin Binding Protein), essential for proper stability of centrioles and ciliogenesis regulation ( 21 ), is associated with diabetic nephropathy ( 22 ), neuroblastoma ( 23 ), and microcephaly ( 24 ). However, MTMR3:: SFI1 fusion has not been previously reported.…”