Primary ciliary dyskinesia (PCD) is a life-long, debilitating condition characterised by persistent respiratory infections attributed to impaired mucociliary clearance. Defects in motile cilia underlie this disease, yet PCD patient-derived myeloid cells, which lack motile cilia, display disrupted migration and microtubule localisation. It has, therefore, been hypothesized that immune dysfunction contributes to chronic lung infections of PCD patients. Until now, the underlying mechanisms of PCD-associated myeloid defects have been unclear.
In this issue, Joshua Waxman and colleagues (Falkenberg et al., 2021) investigate the enigma of myeloid cell defects in PCD and link it to a novel function of coiled-coil domain-containing protein 103 (CCDC103) that is independent of motile cilia. In humans, CCDC103 is one of the genes mutated in PCD; the protein is an axonemal dynein assembly factor important for facilitating ciliary motion. The authors initially discovered that Ccdc103 is expressed in human and zebrafish myeloid cells, where it colocalises with cytoplasmic microtubules. In zebrafish ccdc103/schmalhans (smh) mutants - an established model for PCD - proliferation of macrophages and neutrophils is reduced, and cells show abnormal morphology and abrogated migration. Importantly, all of these effects can be rescued by low doses of the microtubule-stabilising agent paclitaxel, suggesting that Ccdc103 exerts its function by affecting microtubule stability in myeloid cells.
Indeed, by using the human promyelocytic leukemia HL-60 cell line, Falkenberg et al. identified a direct interaction between CCDC103 and the known microtubule-binding protein sperm associated antigen 6 (SPAG6), which is known to promote cellular processes similar to those of CCDC103 in both ciliated and non-ciliated cells. The authors also showed that zebrafish spag6 mutants display similar myeloid defects as those found in smh mutants. The interaction between Ccdc103 and Spag6 is dependent on a functioning microtubule network. This suggests that Ccdc103 mediates its effects through anchoring proteins, such as Spag6, at microtubules to facilitate their function. Crucially, in CCDC103 this interaction is abrogated by PCD-associated mutations, indicating it is involved in PCD pathology.
Taken together, the authors have uncovered a novel function of CCDC103 that is independent of motile cilia, and which begins to explain PCD-associated myeloid defects. As this function is disrupted by PCD-associated mutations in CCDC103, mutations in other PCD-associated proteins might also contribute to myeloid cell dysfunction. By expanding PCD research into that of myeloid cell function, this study opens up new therapeutic avenues to treat this life-long condition.