Contributions of Ccr4 and Gcn2 to the Translational Response of
            <i>C. neoformans</i>
            to Host-Relevant Stressors and Integrated Stress Response Induction

Knowles, Corey M.; Goich, David; Bloom, Amanda L. M.; Kalem, Murat C.; Panepinto, John C.

doi:10.1128/mbio.00196-23

Cited by 2 publications

(6 citation statements)

References 65 publications

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“…4). Consistent with our previous studies [9,10,12], we observed translation repression in the WT upon thermal stress, with an increase in the free 60S ribosomal subunits and repression in the polysomes (Fig. 4A).…”

Section: Gcn2 Drives An Altered Translational Response To Thermal Str...supporting

confidence: 92%

“…Since our previous work has also established the Gcn2 pathway as a key regulator of translation in C. neoformans during stress [10], we began our studies by investigating whether eIF2α phosphorylation was increased in a Hog1 deletion mutant by western blotting (Fig. 1).…”

Section: Loss Of Hog1 Increases Phosphorylated Eif2α During Thermal S...mentioning

confidence: 99%

“…1), we next investigated whether stimulating the Hog1 pathway is sufficient to alter levels of phospho-eIF2α during stress. Since thermal stress acts on the Hog1 and Gcn2 pathways simultaneously [10,12], this stressor was not useful for testing cause-and-effect relationships between these pathways. To overcome this, we used the drug fludioxonil, which stimulates the Hog1 pathway by acting on its upstream regulators [23], and 3-amino-1,2,4-triazole (3-AT), which inhibits histidine biosynthesis resulting in Gcn2 activation.…”

Section: Stimulation Of the Hog1 Pathway Regulates Levels Of P-eif2αmentioning

confidence: 99%

“…Defects in this process in fungal pathogens, called translatome reprogramming, are associated with impaired stress adaptation and attenuated virulence [4]. We've documented reprogramming in response to several stressors that are relevant to infection in C. neoformans, and have identified key regulators of this process [7][8][9][10]. For example, C. neoformans lacking the major mRNA deadenylase, Ccr4, is unable to repress abundant growth-associated mRNAs and exhibits defects in survival at mammalian core temperature and attenuated virulence [9,11].…”

Section: Introductionmentioning

confidence: 99%

“…The Atf1/Gcn4 transcriptional regulon, known as the integrated stress response (ISR), encodes proteins that are important for maintenance of amino acid biosynthesis, tRNA charging, and redox balance [22]. We recently characterized the role of Gcn2 and the ISR during stress in C. neoformans, and showed that this pathway is induced by mammalian core temperature [10].…”

Section: Introductionmentioning

confidence: 99%

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Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling inC. neoformansduring thermal stress

Goich,

Bloom,

Duffy

et al. 2024

Preprint

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The fungusCryptococcus neoformansis an opportunistic pathogen of people that reprograms its translatome to facilitate adaptation and virulence within the host. We studied the role of Hog1/p38 in reprogramming translation during thermal stress adaptation, and found that this pathway acts on translation via crosstalk with the Gcn2 pathway, a well-studied regulator of general translation control. Using a combination of molecular assays and phenotypic analysis, we show that increased output from the Gcn2 pathway in a Hog1 deletion mutant is associated with rescue of thermal stress adaptation at both molecular and phenotypic scales. We characterize known outputs of the Hog1 pathway during thermal stress as either Gcn2-dependent or Gcn2-independent, and demonstrate that Hog1 activation regulates the Gcn2 pathway even in the absence of thermal stress. Finally, we implicate this phenomenon in another Hog1-regulated process, morphogenesis, and recapitulate Hog1-Gcn2 crosstalk in the distantly related fungal pathogen,Candida albicans.Our results point to an important link between the stress response machinery and translation control, and clarify the etiology of phenotypes associated with Hog1 deletion. More broadly, this study highlights complex interplay between core conserved signal transduction pathways and the utility of molecular assays to better understand how these pathways are connected.ImportanceCryptococcus neoformansis an opportunistic pathogen of people that causes deadly cryptococcal meningitis, which is is responsible for an estimated 19% of AIDS-related mortality. When left untreated, cryptococcal meningitis is uniformly fatal, and in patients receiving the most effective antifungal regimens, mortality remains high. Thus, there is a critical need to identify additional targets that play a role in adaptation to the human host and virulence. This study explores the role of the stress response kinases Hog1 and Gcn2 in thermoadaptation, which is pre-requisite for virulence. Our results show that compensatory signaling occurs via the Gcn2 pathway when Hog1 is deleted, and that disruption of both pathways increases sensitivity to thermal stress. Importantly, our study highlights the insufficiency of using single gene deletion mutants to study gene function, since many phenotypes associated with Hog1 deletion were driven by Gcn2 signaling in this background, rather than loss of direct Hog1 activity.

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Section: Gcn2 Drives An Altered Translational Response To Thermal Str...supporting

confidence: 92%

Section: Loss Of Hog1 Increases Phosphorylated Eif2α During Thermal S...mentioning

confidence: 99%

Section: Stimulation Of the Hog1 Pathway Regulates Levels Of P-eif2αmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling inC. neoformansduring thermal stress

Goich,

Bloom,

Duffy

et al. 2024

Preprint

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MARCH2, a T cell specific factor that restricts HIV-1 infection

Umthong,

Timilsina,

D’Angelo

et al. 2024

PLoS Pathog

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Membrane-associated RING-CH (MARCH) 2 is a member of the MARCH protein family of RING-CH finger E3 ubiquitin ligases that play important roles in regulating the levels of proteins found on the cell surface. MARCH1, 2 and 8 inhibit HIV-1 infection by preventing the incorporation of the envelope glycoproteins into nascent virions. However, a better understanding on the mechanism utilized by MARCH proteins to restrict HIV-1 infection is needed. In this report, we identify an amino acid in human MARCH2, absent in mouse MARCH2, critical for its antiretroviral function. Moreover, we map the domains of human MARCH2 critical for restricting as well as binding to the HIV-1 envelope glycoproteins. In addition, we demonstrate that MARCH2 is present inside nascent virions and reduces particle infectivity by blocking virus entry in a RING-CH-independent manner. Finally, we show that MARCH2 acts as an HIV-1 restriction factor only in primary CD4+ T cells and can prevent cell-to-cell transmission of HIV-1. Our findings reveal important new aspects of the antiviral mechanism utilized by human MARCH2 to restrict HIV-1 that have potential implications to all MARCH proteins with antiviral functions and their viral targets.

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Contributions of Ccr4 and Gcn2 to the Translational Response of C. neoformans to Host-Relevant Stressors and Integrated Stress Response Induction

Abstract: Cryptococcus neoformans is a human pathogen capable of causing devastating infections. It must rapidly adapt to changing environments as it leaves its niche in the soil and enters the human lung.

Cited by 2 publications

References 65 publications

Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling inC. neoformansduring thermal stress

Gcn2 rescues reprogramming in the absence of Hog1/p38 signaling inC. neoformansduring thermal stress

MARCH2, a T cell specific factor that restricts HIV-1 infection

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