C. elegans huntingtin, htt-1, promotes robust autophagy induction and survival under stress conditions

Abstract

Huntingtin (HTT) is the gene responsible for Huntingtons disease (HD), a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion mutation. While HD pathogenesis has traditionally been attributed to the toxic gain-of-function effects of mutant huntingtin (mHTT), increasing evidence underscores the critical role of wild-type HTT loss-of-function. Understanding the physiological roles of HTT is essential for elucidating HD mechanisms and developing effective therapeutic strategies. The C. elegans htt-1 gene, an ortholog of human HTT, remains largely uncharacterized. Here, we demonstrate that htt-1 promotes survival under stress conditions that requires autophagy as a defense mechanism. Specifically, we identify intestinal htt-1 as a key regulator of C. elegans survival during Pseudomonas aeruginosa PA14 infection. Our findings reveal that htt-1 functions downstream of the MPK-1/ERK pathway to induce systemic autophagy and enhance host defense during immune challenges. Moreover, expression of wild-type human HTT in htt-1 mutant worms rescues the survival defect during PA14 infection. Expression of mutant human HTT, on the other hand, exacerbates survival deficits, underscoring the conserved function of HTT across species. Additionally, we found that htt-1 affects survival and autophagy under heat shock stress conditions. These results establish htt-1 as a critical regulator of survival and autophagy in response to both pathogenic bacterial infection and thermal stress. Author summaryHuntingtin plays essential roles in selective autophagy across various organisms, including Drosophila, mice, and humans. Notably, the C. elegans huntingtin ortholog, htt-1, remains largely uncharacterized. Here, we describe a novel pro-survival role htt-1 in stress resistance. We show that htt-1 mutants exhibit significantly reduced survival during Pseudomonas aeruginosa infection. Expression of wild-type human HTT rescues the reduced survival of htt-1 mutants, whereas mutant HTT further exacerbates the phenotype. These findings establish C. elegans htt-1 as a valuable model for studying huntingtin biology and its roles in stress resistance. Downregulation of ERK in htt-1 mutants had no additional effect on survival, suggesting that htt-1 functions downstream of ERK. Interestingly, htt-1 mutants display reduced autophagy, indicating that htt-1 functions in the ERK-autophagy signaling cascade during infection. Mechanistically, we propose that htt-1 regulates autophagy at the protein level. HTT-1 remains cytoplasmic, and autophagy-related gene transcripts remain stable, without downregulation, in htt-1 mutants following infection. Additionally, htt-1 mutants exhibit reduced survival and impaired autophagy under heat stress. These results suggest that htt-1 may have a broader role in stress resilience extending beyond immune defense.