Welsh, Christofer et al. (2021) International Worm Meeting "Disruption of Golgi function induces pathogen response gene expression"

Welsh, Christofer, Walker, Amy

[International Worm Meeting, 2021]

Each secretory pathway organelle has a distinct configuration of phospholipids and resident proteins in addition to separable stress pathways. These stress pathways activate restorative transcriptional programs when lipid ratios become unbalanced, or protein function fails. We and others have noticed that a common set of genes are activated by bacterial pathogens, disruption in lipid synthesis or induction of ER stress. Here, we show that these immunity-linked genes (ILGs) are also activated upon disruption of the ADP-ribosylation factor ARF-1, a key regulator of Golgi secretory function. We have previously found that ARF-1 activity is blocked by changes in membrane lipid levels, which suggests that altered lipid levels in secretory organelles other than the ER can also stimulate these ILGs as part of a stress response.

Welsh, Christofer M et al. (2021) International Worm Meeting "Characterization of a membrane stress response to stabilize intracellular trafficking in C. elegans"

Walker, Amy K, Bulcha, Jote T, Walhout, Albertha J M, Welsh, Christofer M

[International Worm Meeting, 2021]

Membranes form the outer boundaries of cells and their organelles. Some organelles, such as the endoplasmic reticulum (ER), mitochondria and Golgi apparatus, are defined by the structure and composition of their membranes. Dysfunction in the structure or function of membrane-defined organelles results in activation of stress responses to stabilize and restore the organelles. Organelle stress responses can affect lifespan and the aging process and may be activated in other physiological conditions such as during lipid accumulation in metabolic disease. Membrane stress responses in the ER and mitochondria can induce pathologies due to metabolic dysfunction, and as such constitute a public health concern. However, the Golgi stress response, a nascent field of study, has not been as extensively investigated. Using Caenorhabditis elegans and human cell lines, we have found that altering levels of the membrane phospholipid phosphatidylcholine (PC) changes Golgi function by inactivating a key intracellular trafficking enzyme, the small GTPase ARF-1/ARF1. Furthermore, work in our lab has shown that dysfunctional COPI retrograde as well as COPII anterograde trafficking induces upregulation of the lowly expressed warf-1/arf-1.1 in C. elegans. Additionally, our data indicates that upregulation of warf-1 is dependent on LET-607/CREB3. We hypothesize that changes in the lipid composition of the Golgi apparatus, such as reduced levels of PC, activates a dual stress response to restore lipid homeostasis by SBP-1/SREBP1 and stabilize Golgi trafficking by the compensatory WARF-1. Warf-1 is unique to C. elegans, however, in many respects its regulation and function are reminiscent of human ARF4. Like ARF4, warf-1 is upregulated in response to dysfunctional COPI retrograde trafficking by LET-607/CREB3. Furthermore, the N-terminal end of WARF-1 resembles that of ARF4 more closely than ARF1. It has been shown that this domain is required for class II ARFs to associate with ERGIC membranes during dysfunctional intracellular trafficking Consequently, investigating the warf-1 membrane stress response will enhance our understanding of how human ARF4 functions during altered membrane lipid composition and stress to intracellular trafficking.

Levin ED et al. (2009) Neurotoxicology "Genetic aspects of behavioral neurotoxicology."

Kirshner A, Eddins D, French R, Helmcke K, Page GP, Linney E, Lnenicka G, Berger K, Welsh-Bohmer KA, Corl AB, Levin ED, Hirsch HV, Aschner M, Bartlett S, Possidente B, Hayden KM, Chen L, Possidente D, Ruden D, Heberlein U

[Neurotoxicology, 2009]

Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.