BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. BNip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and elevated mitochondrial ROS increases the expression of Hif-1a and Hif target genes, including those involved in glycolysis and angiogenesis-two processes that are also markedly increased in BNip3-null tumors. Glycolysis inhibition attenuates the growth of BNip3-null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple-negative breast cancer (TNBC). These studies show that mitochondrial dysfunctioncaused by defects in mitophagy-can promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment.
N6-methyladenosine (m6A) is a reversible and abundant internal modification of messenger RNA (mRNA) and long noncoding RNA (lncRNA) with roles in RNA processing, transport, and stability. Although m6A does not preclude Watson-Crick base pairing, the N6-methyl group alters the stability of RNA secondary structure. Since changes in RNA structure can affect diverse cellular processes, the influence of m6A on mRNA and lncRNA structure has the potential to be an important mechanism for m6A function in the cell. Indeed, an m6A site in the lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was recently shown to induce a local change in structure that increases the accessibility of a U5-tract for recognition and binding by heterogeneous nuclear ribonucleoprotein C (HNRNPC). This m6A-dependent regulation of protein binding through a change in RNA structure, termed ‘m6A-switch,’ affects transcriptome-wide mRNA abundance and alternative splicing. To further characterize this first example of an m6A-switch in a cellular RNA, we used nuclear magnetic resonance (NMR) and Förster resonance energy transfer (FRET) to demonstrate the effect of m6A on a 32-nucleotide RNA hairpin derived from the m6A-switch in MALAT1. The observed imino proton NMR resonances and FRET efficiencies suggest that m6A selectively destabilizes the portion of the hairpin-stem where the U5-tract is located, increasing the solvent accessibility of the neighboring bases while maintaining the overall hairpin structure. The m6A-modified hairpin has a predisposed conformation that resembles the hairpin conformation in the RNA–HNRNPC complex more closely than the unmodified hairpin. The m6A-induced structural changes in the MALAT1 hairpin can serve as a model for a large family of m6A-switches that mediate the influence of m6A on cellular processes.
Human Vγ9Vδ2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vγ9Vδ2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vγ9Vδ2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. However, it is unknown how downstream events can ultimately lead to T cell activation. Here, using NMR spectrometry and molecular dynamics (MD) simulations, we characterize a global conformational change in the B30.2 intracellular domain of BTN3A1 induced by pAg binding. We also reveal by crystallography two distinct dimer interfaces in the BTN3A1 full-length intracellular domain, which are stable in MD simulations. These interfaces lie in close proximity to the pAg-binding pocket and contain clusters of residues that experience major changes of chemical environment upon pAg binding. This suggests that pAg binding disrupts a preexisting conformation of the BTN3A1 intracellular domain. Using a combination of biochemical, structural, and cellular approaches we demonstrate that the extracellular domains of BTN3A1 adopt a V-shaped conformation at rest, and that locking them in this resting conformation without perturbing their membrane reorganization properties diminishes pAg-induced T cell activation. Based on these results, we propose a model in which a conformational change in BTN3A1 is a key event of pAg sensing that ultimately leads to T cell activation.human Vγ9Vδ2 T cells | butyrophilin 3A1 | phosphoantigen | conformational change
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