Biology subjects

Zewe, J.

Publications and source records attributed to Zewe, J..

3 recordsLinked to original sources

bioRxiv2024

Neurofilament accumulation disrupts autophagy in giant axonal neuropathy

Neurofilament accumulation is a marker of several neurodegenerative diseases, but it is the primary pathology in Giant Axonal Neuropathy (GAN). This childhood onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that is essential for neurofilament degradation. Using a combination of genetic and RNA interference (RNAi) approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through two mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations sequester the chaperone 14-3-3, a protein responsible for the localization of the transcription factor EB (TFEB), a key regulator of autophagy. This dual disruption of autophagy likely contributes to the pathogenesis of other neurodegenerative diseases with neurofilament accumulations.

neuroscience↗

bioRxiv2019

Probing the Subcellular Distribution of Phosphatidylinositol Reveals a Surprising Lack at the Plasma Membrane

The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these lipids role in health and disease. PPIn are derived from the major structural lipid, phosphatidylinositol (PI). However, although the distribution of most PPIn have been characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, we have used several orthogonal approaches to map the subcellular distribution of PI, including localizing exogenous fluorescent PI, as well as detecting lipid conversion products of endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. We report that PI is broadly distributed throughout intracellular membrane compartments. However, there is a surprising lack of PI in the plasma membrane compared to the PPIn. These experiments implicate regulation of PI supply to the plasma membrane, as opposed to regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM. SummaryZewe et al develop approaches to map the subcellular distribution of the major phospholipid, phosphatidylinositol (PI), revealing that the lipid is present in most membranes except for plasma membrane, where it is mainly found as PI4P and PI(4,5)P2.

cell biology↗

bioRxiv2018

A High Avidity Biosensor Reveals PI(3,4)P2 is Predominantly a Class I PI3K Signaling Product

Class I PI 3-kinase (PI3K) signaling is central to animal growth and metabolism, and disruption of this pathway occurs frequently in cancer and diabetes. However, the specific spatial/temporal dynamics and signaling roles of its minor lipid messenger, phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2], are not well understood. This owes principally to a lack of tools to study this scarce lipid. Here, we developed a high sensitivity genetically encoded biosensor for PI(3,4)P2, demonstrating high selectivity and specificity of the sensor for the lipid. We show that despite clear evidence for class II PI3K in PI(3,4)P2-driven function, the overwhelming majority of the lipid accumulates through degradation of class I PI3K-produced PIP3. However, we show that PI(3,4)P2 is also subject to hydrolysis by the tumor suppressor lipid phosphatase PTEN. Collectively, our results show that PI(3,4)P2 is potentially an important driver of class I PI3K-driven signaling, and provides powerful new tools to begin to resolve the biological functions of this lipid downstream of class I and II PI3K.

cell biology↗