The lysosomal-autophagic pathway is activated by starvation and plays an important role in both cellular clearance and lipid catabolism. However, the transcriptional regulation of this pathway in response to metabolic cues is currently uncharacterized. Here we show that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and exerts a global transcriptional control on lipid catabolism via PGC1α and PPARα. Thus, during starvation a transcriptional mechanism links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the evolution of the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a novel therapeutic strategy for disorders of lipid metabolism.
Animal host defense against infection requires the expression of defense genes at the right place and the right time. To understand such tight control of host defense requires the elucidation of the transcription factors involved. Using an unbiased approach in the model Caenorhabditis elegans, we discovered that HLH-30 (known as TFEB in mammals) is a key transcription factor for host defense. HLH-30 was activated shortly after Staphylococcus aureus infection, and drove the expression of close to 80% of the host response, including antimicrobial and autophagy genes that were essential for host tolerance of infection. TFEB was also rapidly activated in murine macrophages upon S. aureus infection, and was required for proper transcriptional induction of several proinflammatory cytokines and chemokines. Thus, our data suggest that TFEB is a previously unappreciated, evolutionarily ancient transcription factor in the host response to infection.
The timing of the floral transition in Arabidopsis (Arabidopsis thaliana) is influenced by a number of environmental signals. Here, we have focused on acceleration of flowering in response to vegetative shade, a condition that is perceived as a decrease in the ratio of red to far-red radiation. We have investigated the contributions of several known flowering-time pathways to this acceleration. The vernalization pathway promotes flowering in response to extended cold via transcriptional repression of the floral inhibitor FLOWERING LOCUS C (FLC); we found that a low red to far-red ratio, unlike cold treatment, lessened the effects of FLC despite continued FLC expression. A low red to far-red ratio required the photoperiod-pathway genes GIGANTEA (GI) and CONSTANS (CO) to fully accelerate flowering in long days and did not promote flowering in short days. Together, these results suggest a model in which far-red enrichment can bypass FLC-mediated late flowering by shifting the balance between FLC-mediated repression and photoperiodic induction of flowering to favor the latter. The extent of this shift was dependent upon environmental parameters, such as the length of far-red exposure. At the molecular level, we found that far-red enrichment generated a phase delay in GI expression and enhanced CO expression and activity at both dawn and dusk. Finally, our analysis of the contribution of PHYTOCHROME AND FLOWERING TIME1 (PFT1) to shade-mediated rapid flowering has led us to suggest a new model for the involvement of PFT1 in light signaling.
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