The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial

Else, Monica; Blakemore, Stuart J.; Strefford, Jonathan C.; Catovsky, Daniel

doi:10.1038/s41375-021-01165-w

Cited by 8 publications

(4 citation statements)

References 32 publications

(57 reference statements)

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“…This implies that individuals carrying a loss of function mutations in SCF complex genes could be highly susceptible to bacterial infections. Indeed, a recent cohort-based study indicated that almost 43% of the CLL (Chronic Lymphocytic Leukaemia) patients, caused by mutations in the FBXW7 gene, succumb to bacterial pneumonia and sepsis followed by fungal infections (25). Our findings therefore provide an unexpected molecular explanation of the enhanced risk of infections of the CLL patients, especially to respiratory pathogens.…”

Section: Main Textmentioning

confidence: 57%

A novel innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

Apte

Bhutda

Ghosh

et al. 2021

Preprint

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Sensing of pathogens by ubiquitination is critical for maintaining cytosolic sanctity. However, universal ubiquitination targets on bacteria, especially of proteinaceous origin, remain unidentified. Here, we unveil a novel strategy, involving recognition of degron-like motifs for identification of first protein-based ubiquitination substrates on phylogenetically distinct bacteria. Such motifs can form a new class of intra-cytosolic pathogen associated molecular patterns (PAMPs) as their incorporation enables identification of non-ubiquitin targets by host Ub-ligases. We find SCFFBW7 E3-ligase, supported by the regulatory kinase, GSK3β, is crucial for effective pathogen detection and clearance. This may explain the enhanced risk of infections in Chronic Lymphocytic Leukaemia patients bearing FBXW7 mutations. We conclude that exploitation of such ubiquitous pathogen sensing strategy allows conservation of cellular resources and boost anti-microbial immunity.

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Section: Main Textmentioning

confidence: 57%

A novel innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

Apte

Bhutda

Ghosh

et al. 2021

Preprint

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“…Heterozygous mutations in FBXW7, particularly R505C (a critical residue in substrate recognition pocket) variant, trigger multiple carcinomas and lymphocytic leukemia in humans ( 49 , 50 ). A recent cohort-based study indicated that almost 43% of the patients with chronic lymphocytic leukemia (CLL) succumb to bacterial pneumonia and sepsis, followed by fungal infections ( 51 ). This corroborates with our observation of the abrogated ability of host cells bearing FBXW7 mutation to sense and eliminate pathogens.…”

Section: Discussionmentioning

confidence: 99%

An innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

et al. 2023

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Sensing of pathogens by ubiquitination is a critical arm of cellular immunity. However, universal ubiquitination targets on microbes remain unidentified. Here, using in vitro, ex vivo, and in vivo studies, we identify the first protein-based ubiquitination substrates on phylogenetically diverse bacteria by unveiling a strategy that uses recognition of degron-like motifs. Such motifs form a new class of intra-cytosolic pathogen-associated molecular patterns (PAMPs). Their incorporation enabled recognition of nonubiquitin targets by host ubiquitin ligases. We find that SCF FBW7 E3 ligase, supported by the regulatory kinase, glycogen synthase kinase 3β, is crucial for effective pathogen detection and clearance. This provides a mechanistic explanation for enhanced risk of infections in patients with chronic lymphocytic leukemia bearing mutations in F-box and WD repeat domain containing 7 protein. We conclude that exploitation of this generic pathogen sensing strategy allows conservation of host resources and boosts antimicrobial immunity.

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“…FBXW7 (also known as CDC4) is a component of the S-phase kinase-associated protein 1 (SKP1)/CUL1/F-box (SCF) E3 ubiquitin ligase complex, which functions as a tumor suppressor which is frequently altered in cancer [ 187 , 188 ]. It has been reported that loss of FBXW7 in the presence of the BRAF V600E mutation is consequential and sufficient to drive tumorigenesis in mouse models [ 189 ].…”

Section: Regulation Of Targeted Therapy Through Modulating Protein De...mentioning

confidence: 99%

Protein degradation: expanding the toolbox to restrain cancer drug resistance

Hui

Jiang

et al. 2023

J Hematol Oncol

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Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

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The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial

Cited by 8 publications

References 32 publications

A novel innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

A novel innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

An innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins

Protein degradation: expanding the toolbox to restrain cancer drug resistance

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