Innate Host Defense Requires TFEB-Mediated Transcription of Cytoprotective and Antimicrobial Genes

Abstract

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.

Antimicrobial effectors in the nematode Caenorhabditis elegans : an outgroup to the Arthropoda

“…In addition, examination of transgenic worms carrying a translational GFP reporter for LGG-1 revealed that the autophagy machinery is targeted to N. parisii cells [42]. (iii) Infection with the extracellular pathogen S. aureus also activates the expression of several autophagy genes and this activation is dependent on the bHLH transcription factor HLH-30, which is required for the expression of 80% of the transcriptional C. elegans response to S. aureus, including AMP genes [23]. Staphylococcus aureus infection-induced autophagosome formation could be observed by analysis of the localization of GFP-tagged LGG-1 in the C. elegans intestine [23].…”

“…(iii) Infection with the extracellular pathogen S. aureus also activates the expression of several autophagy genes and this activation is dependent on the bHLH transcription factor HLH-30, which is required for the expression of 80% of the transcriptional C. elegans response to S. aureus, including AMP genes [23]. Staphylococcus aureus infection-induced autophagosome formation could be observed by analysis of the localization of GFP-tagged LGG-1 in the C. elegans intestine [23]. Worms in which the autophagy genes lgg-1, unc-51 (homologous to human ULK1) and vps-34 (homologous to human phosphoinositide 3-kinaseVPS34) are knocked down by RNAi are more susceptible to S. aureus-mediated killing.…”

“…Expression of lys-2 is regulated by the GATA transcription factor ELT-2 and the p38 MAPK PMK-1 [72]. The transcription factor HLH-30 influences expression of lys-2, ilys-3, ilys-4, lys-3, lys-5 and lys-10 following S. aureus infection [23]. Based on WormExp [26], we find that lysozyme gene expression is differentially regulated by almost all of the considered microbes (figure 3b; full results in the electronic supplementary material, figure S1).…”

Ectopic fat deposition contributes to age-associated pathology in Caenorhabditis elegans

“…HLH-30/TFEB could also be involved in the regulation of vitellogennins/ lipoproteins modulating lipid homeostasis and ectopic lipid storage under normal and stress-induced conditions. Although HLH-30/TFEB is required under stress conditions to maintain organismal homeostasis and survival (55,80), its function is not restricted to normal conditions. Wild-type nematodes subjected to RNAi against hlh-30 display decreased expression of several autophagy and lysosomal genes.…”

From the Cover: Alterations in Optineurin Expression and Localization in Pre-clinical Parkinson’s Disease Models

“…OPTN expression is known to be regulated by the autophagy regulator transcription factor EB (TFEB) and the inflammatory cytokine TNF-alpha (Nagabhushana et al, 2011;Visvikis et al, 2014). Both autophagic dysfunction and neuroinflammation occur in PD and are linked to pathogenesis (Macchi et al, 2015;Tan et al, 2014).…”