A neuropeptide pathway modulates the endoplasmic reticulum stress in Drosophila melanogaster

Abstract

Temperature is a critical environmental factor that influences animal development and stress responses. In Drosophila melanogaster, elevated temperatures (e.g., 30°C) accelerate larval development but also induce endoplasmic reticulum (ER) stress. To sustain this rapid growth, suppression of ER stress and the unfolded protein response (UPR) within imaginal discs appears to be essential. Indeed, unlike other larval tissues, imaginal discs exhibit a remarkably repressed UPR even under high-temperature conditions such as 37°C. However, the molecular mechanisms underlying this strong suppression of UPR in imaginal discs remain largely unknown. Here, this study identifies the neuropeptide-like precursor 1 (Nplp1) as a key regulator of ER homeostasis in larval imaginal discs exposed to warm temperatures. This work shows that heat induces expression of the Nplp1-RC splice variant specifically in imaginal discs, which suppress activation of PERK, a major UPR sensor. Loss of Nplp1 function results in enhanced PERK–ATF4-Thor signaling, leading to increased apoptosis and elevated expression of Dilp8, a hormone known to inhibit ecdysone biosynthesis and systemic growth. This cascade culminates in reduced cell proliferation, impaired organ development, and developmental arrest at 30°C. Through genetic interaction studies, transcriptome analysis, and hormone rescue experiments, this study demonstrates that Nplp1-RC represses the PERK–ATF4–Yki–Dilp8 axis, thereby supporting ecdysone homeostasis and enabling growth under thermal stress. Nplp1-deficient larvae also show heightened sensitivity to pharmacological ER stressors such as thapsigargin and tunicamycin, whereas expression of Nplp1-RC confers resistance. The findings reveal a previously unrecognized neuropeptide-mediated mechanism that integrates tissue-specific ER stress suppression with systemic hormonal regulation. The heat-induced activation of Nplp1-RC enables developmental progression under stressful environmental conditions, providing insight into how animals achieve thermal resilience through neuroendocrine coordination.