The Aspergillus fumigatus growth determinant Afu6g07200 is the first granulin described in fungi

The Granulin motif is an ancient extracellular growth determinant in eukaryotes but not in fungi. The motif consists of 12 cysteines that give the protein a unique tertiary structure of four stacked β-hairpins. In humans, this domain is related to survival, growth modulation, migration, inflammation, wound repair, and diseases like frontotemporal dementia, Alzheimer's disease, and cancer. The protein encoded by the gene Afu6g07200 of Aspergillus fumigatus shows a domain with predicted granulin structure and is overexpressed during spore germination. Despite low conservation of its amino acid sequence, this domain exhibits the same predicted 3D structure as several human granulins, with the highest confidence (95.4%) being observed with human GRNA. Moreover, this protein is conserved among the Pezizomycotina subdivision. In this study, we demonstrate that this A. fumigatus protein is involved in proliferation, polarization, cell wall integrity, cytoskeletal organization, stress response, and sensing. Fungal granulin is implicated in maintaining the periplasmic space, is related to polarity markers and actin, and plays an essential role in activating MAPK cascades. Furthermore, complementation with human GRNA fulfilled the activities of the fungal protein at morphological and molecular levels. Therefore, this is the first description of a granulin domain in filamentous fungi based on 3D structure and function homology.