Stress signaling pathways for the pathogenicity of Cryptococcus

Abstract

Sensing, responding, and adapting to the surrounding environment are crucial for all living organisms to survive, proliferate, and differentiate in their biological niches. This ability is also essential for Cryptococcus neoformans and its sibling species Cryptococcus gattii, as these pathogens have saprobic and parasitic life cycles in natural and animal host environments. The ability of Cryptococcus to cause fatal meningoencephalitis is highly related to its capability to remodel and optimize its metabolic and physiological status according to external cues. These cues act through multiple stress signaling pathways through a panoply of signaling components, including receptors/sensors, small GTPases, secondary messengers, kinases, transcription factors, and other miscellaneous adaptors or regulators. In this minireview, we summarize and highlight the importance of several stress signaling pathways that influence the pathogenicity of Cryptococcus and discuss future challenges in these areas.

Fig 1

The HOG signaling pathway in C. neoformans. The HOG pathway, mainly consisting of a phosphorelay system (Tco-Ypd1-Ssk1 cascade) and the Ssk2-Pbs2-Hog1 MAPK module, not only senses almost all types of environmental stresses, it regulates virulence factor production (melanin and capsule) and controls ergosterol biosynthesis by regulating ERG gene expression. Although not shown in this figure, the HOG pathway is involved in the response against genotoxic agents, toxic heavy metal and metabolites, and high temperature. To regulate osmotic stress response, a second upstream signaling branch of the Ssk2-Pbs2-Hog1 pathway may exist. Although cross talk exists among HOG, Cpk1, and cAMP/PKA pathways, their detailed mechanism is unknown. Please refer to the text for more details on the regulatory mechanism of the HOG pathway. Black arrows indicate positive regulation or activation, whereas red lines ending in circles indicate negative regulation or repression. Broken arrows or lines indicate potential but unclear regulation. Abbreviations: AMB, amphotericin B, which binds membrane ergosterol and disrupts membrane integrity. PTP, protein tyrosine phosphatases; PP2C, protein phosphatase type 2C.

Fig 2

The Ras, cAMP/PKA, and MSIL signaling pathways in C. neoformans. In C. neoformans, the Ras and cAMP/PKA signaling pathways appear to have limited interconnection in terms of their cellular functions. Most Ras-related phenotypes are mediated mainly through the Rac1- and Cdc24/Cdc42/Ste20 signaling cascades. Although the cAMP/PKA pathway responds to a variety of environmental cues, hardly any corresponding sensors are known, except for the Gpr4 GPCR that senses methionine for mating and capsule-inducing signals. Interestingly, both glucose starvation and glucose addition seem to activate the cAMP/PKA pathway, as laccase induction for melanin synthesis is triggered by glucose starvation in a cAMP/PKA-dependent manner, and a spike in cAMP levels is also observed when glucose is added to the glucose-starved cells. More kinases and transcription factors downstream of PKA remain to be discovered and characterized. Msl1 has roles as a subunit of the chromatin assembly factor (CAF-1) complex and as an adaptor/regulator of the cAMP/PKA (other hitherto unknown) signaling pathways for stress response, mating, and virulence factor regulation (e.g., melanin). Please refer to the text for more details on the regulatory mechanisms of the Ras, cAMP/PKA, and their related signaling pathways. Black arrows indicate positive regulation or activation, whereas red lines ending in circles indicate negative regulation or repression. Broken arrows or lines indicate potential but unclear regulation. Gray type indicates currently unidentified or uncharacterized.

Fig 3

The Ca²⁺/calcineurin, Rim101, and Pkc1/Mpk1 MAPK signaling pathways in C. neoformans. The Ca²⁺/calcineurin, Rim101, and Pkc1/Mpk1 MAPK signaling pathways are mainly involved in the maintenance of cell wall integrity. Besides these pathways, the HOG, Ras, and UPR pathways are also involved in cell wall integrity. The Ca²⁺/calcineurin and Rim101 pathways are two main pH-sensing pathways, although the HOG pathway is also involved in pH sensing because it affects the expression of two cation transporters, ENA1 and NHA1. In the Rim101 pathway, Rim21- and Rim8-like orthologs have not been discovered, and the presence of functional orthologs is unknown. Therefore, pH changes and ion stress may be sensed and delivered by other unknown sensors. Although both Gpr5 and Rim101 are known to be involved in titan cell formation, the role of Gpr5 in pH sensing is unknown. Calmodulin has both Ca²⁺-dependent and -independent functions. Besides Crz1/Sp1, transcription factors targeted by calcineurin remain to be discovered. Pkc1 appears to be a central hub for multiple environmental signals that deliver diverse upstream signals to multibranched downstream signaling pathways, including the Mpk1 MAPK module. Please refer to the main text for more details on the regulatory mechanisms of the Ca²⁺/calcineurin, Rim101, and Pkc1/Mpk1 MAPK signaling pathways. Solid arrows indicate separate, positive regulation or activation, whereas red lines ending in circles indicate negative regulation or repression. Broken arrows or lines indicate potential but unclear regulation. Abbreviations: PI, phosphatidylinositol, DAG, diacylglycerol; IPC, inositol phosphoryl ceramide; ESCRT, endosomal sorting complexes required for transport.

Fig 4

The ER stress response and UPR pathways in C. neoformans. The Cryptococcus UPR pathway consists of the Ire1 kinase, the bZIP transcription factor Hxl1, and their target genes. The UPR pathway responds to ER stress caused by the accumulation of misfolded or unfolded proteins in the ER. In addition, the UPR pathway is involved in cell wall integrity, antifungal drug resistance, and virulence. However, Ire1 has Hxl1-independent roles in certain cellular functions, including capsule biosynthesis. Conversely, Hxl1 appears to have Ire1-independent functions. Please refer to the text for more details on the regulatory mechanism of the UPR pathway. Black arrows indicate positive regulation or activation, whereas red lines ending in circles indicate negative regulation or repression. Broken arrows or lines indicate potential but unclear regulation.