The endocytic adaptor proteins of pathogenic fungi: charting new and familiar pathways

Abstract

Intracellular transport is an essential biological process that is highly conserved throughout the eukaryotic organisms. In fungi, adaptor proteins implicated in the endocytic cycle of endocytosis and exocytosis were found to be important for growth, differentiation, and/or virulence. For example, Saccharomyces cerevisiae Pan1 is an endocytic protein that regulates membrane trafficking, the actin cytoskeleton, and signaling. In Cryptococcus neoformans, a multi-modular endocytic protein, Cin1, was recently found to have pleiotropic functions in morphogenesis, endocytosis, exocytosis, and virulence. Interestingly, Cin1 is homologous to human intersectin ITSN1, but homologs of Cin1/ITSN1 were not found in ascomycetous S. cerevisiae and Candida albicans, or zygomycetous fungi. Moreover, an Eps15 protein homologous to S. cerevisiae Pan1/Ede1 and additional relevant protein homologs were identified in C. neoformans, suggesting the existence of either a distinct endocytic pathway mediated by Cin1 or pathways by either Cin1 or/and Pan1/Ede1 homologs. Whether and how the Cin1-mediated endocytic pathway represents a unique role in pathogenesis or reflects a redundancy of a transport apparatus remains an open and challenging question. This review discusses recent findings of endocytic adaptor proteins from pathogenic fungi and provides a perspective for novel endocytic machinery operating in C. neoformans. An understanding of intracellular trafficking mechanisms as they relate to pathogenesis will likely reveal the identity of novel antifungal targets.

Wsp1 Is Downstream of Cin1 and Regulates Vesicle Transport and Actin Cytoskeleton as an Effector of Cdc42 and Rac1 in Cryptococcus neoformans

“…Previous studies suggested that C. neoformans maintains actin dynamics similar to those of model yeasts (21,47). In wild-type strains, F-actin is present in polarized patches enriched in the early, emerging daughter cell and at the contractile ring ( Fig.…”

“…Cin1 is a multimodular adaptor protein proposed to regulate endocytosis, exocytosis, and signaling through interactions with several other proteins (47). Cin1 activates Cdc42 through the DH (Rho-GEF) domain; Cdc42, in turn, activates Wsp1 to promote Arp2/3-mediated actin polymerization.…”

Wsp1, a GBD/CRIB Domain-Containing WASP Homolog, Is Required for Growth, Morphogenesis, and Virulence of Cryptococcus neoformans

“…Cin1 shares domain architecture and similar functions with human intersectin ITSN1, and homologs of Cin1 cannot be identified in S. cerevisiae or C. albicans, which has Pan1, an archetypal endocytic protein involved in endocytosis, actin cytoskeleton, and signaling (8,36). Wsp1 was shown to interact with Cin1 and Cdc42, indicating these three proteins likely participate in a complex pathway integrating various signals to regulate multiple processes, including endocytosis and exocytosis, actin dynamics, and signaling (35). While a detailed Cin1-mediated endocytic pathway(s) remains to be illustrated, the unique compositions of Cin1 and Wsp1 proteins, as well as the recent identification of SH3 domains specific to basidiomycetous Ste50 (13), all suggest divergent evolution of multidomain adaptor proteins within the fungal phylum.…”

MoVrp1, a putative verprolin protein, is required for asexual development and infection in the rice blast fungus Magnaporthe oryzae

“…Constant delivery of vesicles and endocytic internalization is required for polarization formation and hyphal growth. As an integral part of the cytoskeleton, actin involves in cell growth, intracellular motility, and cytokinesis in eukaryotic cells6811. Yeast Vrp1 worked in concert with the Arp2/3complex to orchestrate actin organization, as well as endocytosis of the alpha mating factor receptor182425.…”

“…Recently studies showed that endocytosis is conserved from yeast to filamentous fungi, and mammalian cells, which emphasizes the importance of endocytosis for eukaryotic cells5. In yeast and plant pathogenic fungi, endocytosis is extensively involved in cell polarity establishment, hyphal growth, and/or virulence67891011.…”