Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions

Abstract

Plasticity in multicellular organisms involves signaling pathways converting contexts—either natural environmental challenges or laboratory perturbations—into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF–target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16–mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB—the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3. Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name “contextualized transcription.”

Mitochondrial clearance and increased HSF-1 activity are coupled to promote longevity in fasted Caenorhabditis elegans

“… 52 Furthermore, interactions between HLH-30 and HSF-1 have been proposed to govern autophagy, metabolism, and stress resistance. 53 , 54 Therefore, we propose that in response to fasting, HLH-30 promotes organismal robustness through a combination of macroautophagy and mitophagy, which then stimulates HSF-1 activity to further enhance protein folding and degradation.…”

Kombucha Tea-associated Microbes Remodel Host Metabolic Pathways to Suppress Lipid Accumulation

“…Lipophagy, which is a selective form of autophagy that targets lipid droplet TAGs to liberate free fatty acids for further catabolism, is essential for lipid homeostasis and survival in times of low nutrient availability or during states of fasting. In addition to these conditions, homeostatic pathways can dynamically govern lipophagy induction under different nutrient-and stress-related conditions (i.e., fed, fasted, and oxidative stress states) [74]. For example, lipl-3 transcription can be governed by the interplay between the DAF-16/FOXO, PHA-4/FoxA, and HLH-30/TFEB transcription factors in specific contexts [74].…”

“…In addition to these conditions, homeostatic pathways can dynamically govern lipophagy induction under different nutrient-and stress-related conditions (i.e., fed, fasted, and oxidative stress states) [74]. For example, lipl-3 transcription can be governed by the interplay between the DAF-16/FOXO, PHA-4/FoxA, and HLH-30/TFEB transcription factors in specific contexts [74]. We propose that KTM consumption stimulates a fasting-like state in C. elegans to promote lipid utilization via lipophagy; however, future studies will be needed to dissect the precise molecular mechanisms that lead to lipophagy induction in response to KTMs.…”

“…In addition to these conditions, homeostatic pathways can dynamically govern lipophagy induction under different nutrient- and stress-related conditions ( i.e. , fed, fasted, and oxidative stress states) [74]. For example, lipl-3 transcription can be governed by the interplay between the DAF-16/FOXO, PHA-4/FoxA, and HLH-30/TFEB transcription factors in specific contexts [74].…”

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging

“…Among the genes regulated by these factors are lipases lipl-1 and lipl-2 [90, lips-17 {McCormick, 2012 #10478], the fatty acid desaturase fat-5 ( Goudeau et al, 2011 ; McCormick et al, 2012 ), and the fatty acid elongase elo-2 ( McCormick et al, 2012 ). A DAF-16 target, the lipase LIPL-4 ( Wang et al, 2008 ; Mony et al, 2021 ), activates the nuclear hormone receptor NHR-49 (mammalian PPARɑ) ( Folick et al, 2015 ). NHR-49 is necessary for lifespan extension in C. elegans lacking germline, and it upregulates the expression of genes involved in de novo fat synthesis ( Ratnappan et al, 2014 ).…”