CFEM proteins: unique to fungi with essential roles in plant host interactions

Fungal diseases pose a serious threat to agriculture, forestry, and human health sectors and are major contributors to global economic losses. Plant-pathogenic fungi rely on a wide array of molecules that contribute to pathogenicity and virulence; thus, it is critical to understand their roles in plant-fungal interactions to propose control strategies. Among these, CFEM domain-containing proteins, which are unique to fungi primarily within the phyla Ascomycota and Basidiomycota, have diverse functions in the interaction with the host plant. The CFEM domain is characterized by the presence of eight highly conserved cysteine residues, although the proteins show remarkable structural diversity, leading to three functional groups: I) Secretion proteins, II) GPI-anchored proteins, and III) Pth11-like membrane proteins. Current studies have focused on phytopathogenic species, where these proteins not only act as effectors that disrupt the plant immune response but also play roles in maintaining cell wall integrity, heme acquisition, and infection structure formation. However, the diversity among these proteins, as well as their subcellular localization, suggest novel mechanisms remain to be discovered. Herein, we review the phylogenetic distribution of CFEM domain-containing proteins in various species, the relevance of the cysteine residues, and their classification and functional diversity, aiming to provide an integrated approach for a better understanding of their role in fungal cell physiology as well as in the interaction with the host.