RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.
Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.
The century-old embryonal/gametogenesis hypothesis of tumors could link diverse tumors’ malignant features together likely representing the real “stemness” of tumors. However, the genetic evidence to validate abnormal gametogenesis in tumors remains lacking. Here we show that p53 deficiency elicits abnormal gametogenesis from primordial germ cell-like stage to late oocyte-like stage and subsequent parthenogenetic activation. The similar upregulation of abnormal gametogenesis by p53 deficiency is observed both in p53−/− mouse model and cultured cancer cells. Notably, germ cell-like cells isolated from distinct tumors from p53−/− mice and cancer cell lines display potent tumorigenicity potential. Abnormal oogenesis induced by p53 deficiency and then spontaneous parthenogenetic activation endow tumors with imitated embryonic development, life cycle, and therapeutic resistance. Our study establishes the genetic evidence to support embryonal/gametogenesis theory of tumors and reveals a pivotal role of p53 in restricting abnormal gametogenesis that may represent a novel aspect for p53’s tumor suppression.
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