About

Rob Dowen is an Assistant Professor in the Department of Cell Biology and Physiology at the University of North Carolina at Chapel Hill, affiliated with the Integrative Program for Biological and Genome Sciences (iBGS). His research focuses on the appropriate allocation of cellular lipid stores, which is essential for maintaining organismal energy homeostasis. He investigates how this process is coordinated by a network of multi-tissue endocrine signals and how dysregulation can lead to human metabolic syndromes such as cardiovascular disease, obesity, diabetes, and cancer. Dowen's laboratory aims to elucidate the molecular mechanisms governing the storage, metabolism, and intercellular transport of lipids, as well as how these pathways interface with other cellular homeostatic processes like growth and aging. Using C. elegans as a model system, his research combines genetic approaches, including forward and reverse genetic screens and CRISPR, with genomic methodologies such as ChIP-Seq, mRNA-Seq, and DNA-Seq to identify new components and mechanisms of metabolic regulation.

Research topics

• Cell biology
• Biology
• Biochemistry
• Genetics
• Neuroscience
• Computational biology

Selected publications

• The TWK-26/KCNK3 potassium channel and FLR-4 protein kinase coordinate nutrient absorption in the <i>C. elegans</i> intestine

  Genetics · 2026-02-17

  articleOpen accessSenior author

  Ion channels are necessary for proper water and nutrient absorption in the intestine, thereby supporting cellular metabolism and organismal growth. While a role for Na+ co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K+ uniporters function in this process is poorly understood. Mutations in the Caenorhabditis elegans genes drl-1 and flr-4, which encode two unique kinases that are components of a mitogen-activated protein kinase (MAPK) pathway, or the flr-1 Na+ ion channel, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes. Here, we show that a gain-of-function mutation in twk-26, which encodes a 2-pore domain K+ ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects caused by loss of DRL-1, FLR-4, or FLR-1 signaling. We reveal that these phenotypes likely arise from impaired intestinal amino acid absorption, which is restored upon activation of TWK-26. Furthermore, we show that loss of flr-4 disrupts intracellular and extracellular pH gradients, suggesting that the FLR-4 pathway may be necessary to maintain intestinal ion homeostasis and facilitate nutrient absorption. Importantly, the altered pH gradients in the flr-4 mutant are partially restored by the twk-26 gain-of-function mutation. Thus, this study uncovers a new role for the TWK-26 ion channel in governing intestinal physiology and metabolism.

  PublisherDOI

• Stress-dependent activation of PQM-1 orchestrates a second-wave proteostasis response for organismal survival

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-14

  preprintOpen access

  Stress responses are controlled by specialized stress-responsive proteostasis transcription factors that rapidly upregulate protein quality components to re-establish protein homeostasis and safeguard survival. Here we show that the zinc finger transcription factor PQM-1 is crucial for stress survival in response to thermal and oxidative challenges. We provide mechanistic insight into the regulation of PQM-1 during stress that depends on ILS-DAF-16 signaling, as well as phosphorylation on threonine residue 268 that is located within a conserved AKT motif. Our data show that in reproductively mature adults and during well-fed conditions, PQM-1 induction requires DAF-16 and occurs during the recovery period post heat shock. Moreover, PQM-1 co-localizes with DAF-16 in the nucleus during the stress recovery phase. This regulatory dependency on DAF-16 is bypassed under dietary restriction, allowing PQM-1 to promote stress resilience independent of the ILS pathway. During both conditions, PQM-1 is crucial for the upregulation of cytosolic and endoplasmic reticulum stress response genes required for organismal recovery and stress resilience. Our transcriptional and bioinformatic analysis reveals that PQM-1 regulates a distinct set of target genes during the stress recovery phase, suggesting that PQM-1 may be involved in vital secondary wave stress response. Thus, our findings uncover a previously unrecognized mechanism of stress-dependent PQM-1 activation that integrates multiple environmental cues to ensure proteostasis and organismal survival.

  PublisherOA PDFDOI

• Loss of the vitellogenins confers a fitness disadvantage but does not impact brood size in C. elegans

  PubMed · 2025-08-05

  articleOpen accessSenior author

  animals. This strain offers a new model for studying how vitellogenesis impacts reproductive and organismal fitness.

  PublisherOA PDFDOI

• Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis

  Cell Reports · 2025-01-01 · 2 citations

  articleOpen accessSenior author

  Organisms allocate energetic resources between essential cellular processes to maintain homeostasis and, in turn, maximize fitness. The nutritional regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in Caenorhabditis elegans. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor TRA-1/GLI, but rather via non-canonical signaling that engages mammalian target of rapamycin complex 2 (mTORC2). Hh mutants display impaired lipid homeostasis, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we find that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation to modulate lipid homeostasis. Our findings reveal a non-canonical role for Hh signaling in lipid metabolism via regulation of core homeostatic pathways.

  PublisherDOI

• The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans

  UNC Libraries · 2024-07-06

  articleOpen access

  The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the Caenorhabditis elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6, a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

  PublisherDOI

• The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis in C. elegans

  Frontiers in Cell and Developmental Biology · 2024-06-14 · 1 citations

  articleOpen accessSenior authorCorresponding

  The molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified the Caenorhabditis elegans F-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations in fbxl-5 partially suppress the vitellogenesis defects observed in the heterochronic mutants lin-4 and lin-29, both of which ectopically express fbxl-5 at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest that fbxl-5 functions in concert with cul-6 , a cullin gene, and the Skp1-related gene skr-3 to regulate vitellogenesis. Additionally, fbxl-5 acts genetically upstream of rict-1 , which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.

  PublisherOA PDFDOI

• Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-07 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Organisms must appropriately allocate energetic resources between essential cellular processes to maintain homeostasis and in turn, maximize fitness. The nutritional and homeostatic regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern cellular metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis in C. elegans . We find that expression of two Hh ligands, GRD-3 and GRD-4, is controlled by the LIN-29/EGR transcription factor in the hypodermis, where the Hh secretion factor CHE-14/Dispatched also facilitates non-cell autonomous Hh signaling. We demonstrate, using C. elegans and mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor, TRA-1/GLI, but rather through non-canonical signaling that engages mTOR Complex 2 (mTORC2) in the intestine. Hh mutants display impaired lipid homeostasis, including reduced lipoprotein synthesis and fat accumulation, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we found that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation and that both pathways act together to modulate of lipid homeostasis. Our findings show a non-canonical role for Hedgehog signaling in lipid metabolism via regulation of core homeostatic pathways and reveal a new mechanism by which developmental timing events govern metabolic decisions.

  PublisherOA PDFDOI

• A novel gain-of-function mutation in sgk-1 partially suppresses mTORC2 defects

  PubMed · 2024-02-20 · 1 citations

  articleOpen accessSenior author

  This allele will be useful in further dissecting the mTORC2 pathway and provides new insight into the role of this conserved residue in regulating SGK-1 kinase activity.

  PublisherOA PDFDOI

• The TWK-26/KCNK3 potassium channel and FLR-4 protein kinase coordinate nutrient absorption in the <i>C. elegans</i> intestine

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-07

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Ion channels are necessary for proper water and nutrient absorption in the intestine, thereby supporting cellular metabolism and organismal growth. While a role for Na + co-transporters and pumps in intestinal nutrient absorption is well defined, how individual K + uniporters function in this process is poorly understood. Using Caenorhabditis elegans , we show that a gain-of-function mutation in twk-26 , which encodes a two-pore domain K + ion channel orthologous to human KCNK3, facilitates nutrient absorption and suppresses the metabolic and developmental defects caused by loss of DRL-1/FLR-4 signaling. Mutations in drl-1 and flr-4, which encode two unique kinases that are components of a mitogen-activated protein kinase (MAPK) pathway, and the downstream flr-1 Na + ion channel, cause severe growth defects, reduced lipid storage, and a dramatic increase in autophagic lysosomes, which mirror dietary restriction phenotypes. We reveal that this dietary restriction phenotype is likely the result of impaired intestinal amino acid absorption, which is restored upon activation of TWK-26. Furthermore, we show that loss of flr-4 disrupts intracellular and extracellular pH gradients, suggesting that the FLR-4 pathway may be necessary to maintain intestinal ion homeostasis and facilitate nutrient absorption. The altered pH gradients in the flr-4 mutant are partially restored by activation of TWK-26, demonstrating a novel role for this K + ion channel in governing intestinal physiology and metabolism.

  PublisherOA PDFDOI

• Stress-Induced Nuclear Accumulation and Activity of PQM-1 is Divergently Controlled by Insulin-Like Signaling and Dietary Restriction

  SSRN Electronic Journal · 2024-01-01

  preprintOpen access
  PublisherDOI

Frequent coauthors

• Chi Zhang

  16 shared

• Jack E. Dixon

  16 shared

• Taiowa A. Montgomery

  Colorado State University

  16 shared

• Ellen Youngsoo Rim

  University of Otago

  16 shared

• Carolyn M. Phillips

  University of Southern California

  16 shared

• Sylvia E. J. Fischer

  Harvard University

  16 shared

• Gary Ruvkun

  Brandeis University

  13 shared

• Peter C. Breen

  Harvard University

  12 shared