Abstract The Integrated Stress Response (ISR) helps metazoan cells adapt to cellular stress by limiting the availability of initiator methionyl-tRNA for translation. Such conditions paradoxically stimulate translation ATF4 mRNA through a regulatory 5′ leader sequence with multiple upstream Open Reading Frames (uORFs), thereby activating stress-responsive gene expression. Here, we report identification two critical regulators such induction, noncanonical initiation factors eIF2D and DENR ....

Membrane contact sites between organelles are important for maintaining cellular lipid homeostasis. Members of the recently identified family bridge-like transfer proteins (BLTPs) span opposing membranes at these to enable rapid bulk lipids organelles. While VPS13 and ATG2 members use organelle-specific adaptors membrane targeting, mechanisms that regulate other transporters remain unknown. Here, we identify conserved protein Ybl086c, which name Hoi1 (Hob interactor 1), as an adaptor targets...

Abstract Background Bridge‐like lipid transfer proteins (BLTPs) mediate bulk transport at membrane contact sites. Mutations in BLTPs are linked to both early‐onset neurodevelopmental and later‐onset neurodegenerative diseases, including movement disorders. The tissue specificity temporal requirements of disease pathogenesis remain poorly understood. Objective objective this study was determine tissue‐specific aging‐dependent roles for VPS13A BLTP2 using Drosophila models. Methods We...

ABSTRACT Membrane contact sites are critical junctures for organelle signaling and communication. Endoplasmic reticulum–plasma membrane (ER–PM) were the first to be described; however, protein composition molecular function of these is still emerging. Here, we leverage yeast Drosophila model systems uncover a novel role Hobbit (Hob) proteins at ER–PM sites. We find that localizes in both cells larval salivary glands, this localization mediated by an N-terminal ER anchor conserved C-terminal...

Abstract Caspases perform critical functions in both living and dying cells; however, how caspases physiological without killing the cell remains unclear. Here we identify a novel function of at cortex Drosophila salivary glands. In glands, activation initiator caspase dronc triggers cortical F-actin dismantling, enabling glands to stretch as they accumulate secreted products lumen. We demonstrate that tango7 , not canonical Apaf-1-adaptor dark regulates activity cortex; contrast, is...

ABSTRACT All animals must coordinate growth rate and timing of maturation to reach the appropriate final size. Here, we describe hobbit, a novel conserved gene identified in forward genetic screen for Drosophila with small body hobbit is highly throughout eukaryotes, but its function remains unknown. We demonstrate that mutant have systemic defects because they fail secrete insulin. Other regulated secretion events also animals, including mucin-like ‘glue’ protein from larval salivary...

Regulated exocytosis is an essential process whereby specific cargo proteins are secreted in a stimulus-dependent manner. Cargo-containing secretory granules synthesized the trans-Golgi network (TGN); after budding from TGN, undergo modifications, including increase size. These changes occur during poorly understood called granule maturation. Here, we leverage Drosophila larval salivary glands as model to characterize novel role for Rab GTPases We find that size ∼300-fold between biogenesis...

The Pax6 transcription factor is considered the master control gene for eye formation because (1) it present within genomes and retina/lens in all seeing animals; (2) severe retinal defects accompany its loss; genes have ability to substitute one another across animal kingdom; (4) are capable of inducing ectopic eye/lens flies mammals. Many roles were first elucidated Drosophila through studies eyeless (ey), which controls both growth entire eye-antennal imaginal disc fate specification eye....

The eyes absent (eya) gene of the fruit fly, Drosophila melanogaster, is a member an evolutionarily conserved regulatory network that controls eye formation in all seeing animals. loss eya leads to complete elimination compound while forced expression non-retinal tissues sufficient induce ectopic formation. Within developing retina expressed dynamic pattern and involved tissue specification/determination, cell proliferation, apoptosis, fate choice. In this report we explore mechanisms by...

ABSTRACT Intracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process especially demanding in professional secretory cells, which synthesize secrete massive quantities cargo via regulated exocytosis. The Drosophila larval salivary glands are composed cells that mucin at onset metamorphosis. Using as model system, we have identified role highly conserved retromer complex granule membrane...

Increasing evidence in animal models and humans shows that sympathetic nerve activity controls ovarian androgen biosynthesis follicular development. Thus, participates the development hyperandrogenism characteristics of polycystic ovary syndrome, which is most prevalent pathology women during their reproductive years. In this study, we mimic rat via "in vivo" stimulation with isoproterenol (ISO), a β-adrenergic receptor agonist, test for condition. We also determine whether effect can be...

ABSTRACT Background Bridge-like lipid transfer proteins (BLTPs) mediate bulk transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity temporal requirements of disease pathogenesis remain poorly understood. Objectives To determine the age-of-onset tissue-specific roles VPS13A BLTP2 disorder using Drosophila models. Methods We generated knockdowns...

A common occurrence in metazoan development is the rise of multiple tissues/organs from a single uniform precursor field. One example anterior forebrain vertebrates, which produces eyes, hypothalamus, diencephalon, and telencephalon. Another instance Drosophila wing disc, generates adult blade, hinge, thorax. Gene regulatory networks (GRNs) that are comprised signaling pathways batteries transcription factors parcel undifferentiated field into discrete territories. This simple model...

ABSTRACT Intracellular trafficking is a basic and essential cellular function required for delivery of proteins to the appropriate subcellular destination; this process especially demanding in professional secretory cells, which synthesize secrete massive quantities cargo via regulated exocytosis. The Drosophila larval salivary glands are cells that mucin at onset metamorphosis. Using as model system, we have identified role highly conserved retromer complex granule membrane proteins. We...

Bridge-like lipid transfer proteins (BLTPs) are a novel family of transporters that engage in bulk movement lipids at organelle membrane contact sites. Mutations several the BLTPs associated with human disease. Although recent work has begun to uncover mechanisms by which move lipids, much remains unknown about how BLTP-dependent function is regulated. Our identified subcellular targeting as critical mechanism regulates BLTP function. Using combination silico, vitro, and vivo approaches, we...

Nonvesicular transfer of lipids at membrane contact sites (MCS) has recently emerged as a critical process for cellular function. Lipid proteins (LTPs) mediate this unique transport mechanism, and although several LTPs are known, the complement these continues to expand. Our recent work revealed highly conserved but poorly characterized Hobbit/Hob novel, putative endoplasmic reticulum-plasma (ER-PM) sites. Using both S. cerevisiae D. melanogaster model systems, we demonstrated that Hob...

ABSTRACT Membrane contact sites are critical junctures for organelle signaling and communication. Endoplasmic reticulum-plasma membrane (ER-PM) were the first to be described; however, protein composition molecular function of these is still emerging. Here, we leverage yeast Drosophila model systems uncover a novel role Hobbit/Hob proteins at ER-PM sites. We find that Hobbit localizes in both cells larval salivary glands, this localization mediated by an N-terminal ER anchor conserved...

ABSTRACT Regulated exocytosis is an essential process whereby professional secretory cells synthesize and secrete specific cargo proteins in a stimulus-dependent manner. Cargo-containing granules are synthesized the trans-Golgi Network (TGN); after budding from TGN, undergo many modifications, including dramatic increase size. These changes occur during poorly understood called granule maturation. Here we leverage of Drosophila larval salivary glands as model system to characterize novel...