Biology subjects

Delclaux, I.

Publications and source records attributed to Delclaux, I..

3 recordsLinked to original sources

bioRxiv2023

Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process, dependent upon two tRNASec isodecoders differing by a single 2-O-ribose methylation, called Um34. We characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, Loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and have decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.

cancer biology↗

bioRxiv2023

Lymphatic vessel transit seeds precursors to cytotoxic resident memory T cells in skin draining lymph nodes

Resident memory T cells (TRM) provide rapid, localized protection in peripheral tissues to pathogens and cancer. While TRM are also found in lymph nodes (LN), how they develop during primary infection and their functional significance remains largely unknown. Here, we track the anatomical distribution of anti-viral CD8+ T cells as they simultaneously seed skin and LN TRM using a model of skin infection with restricted antigen distribution. We find exquisite localization of LN TRM to the draining LN of infected skin. LN TRM formation depends on lymphatic transport and specifically egress of effector CD8+ T cells that appear poised for residence as early as 12 days post infection. Effector CD8+ T cell transit through skin is necessary and sufficient to populate LN TRM in draining LNs, a process reinforced by antigen encounter in skin. Importantly, we demonstrate that LN TRM are sufficient to provide protection against pathogenic rechallenge. These data support a model whereby a subset of tissue infiltrating CD8+ T cells egress during viral clearance, and establish regional protection in the draining lymphatic basin as a mechanism to prevent pathogen spread. One Sentence SummaryT cell egress out of virally infected skin via afferent lymphatic vessels seeds CD8+ resident memory T cells in the draining lymph node.

immunology↗

bioRxiv2023

NADK Isoform 3 promotes oxidative stress resistance and melanoma metastasis

Metastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade. Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity. NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis. We have found that metastatic melanoma cells have increased levels of both NADPH and NADP+ suggesting increased de novo biosynthesis of NADP+. De novo biosynthesis of NADP+ occurs through a single enzymatic reaction catalyzed by NAD+ kinase (NADK). Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis. We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1. We have found that Isoform 3 is transcriptionally upregulated by oxidative stress through the action of NRF2. Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.

cancer biology↗