PhD Exit Seminar – Sara Hegazi (Cheng and Levine Labs)

Regulation of Biological Timekeeping and Secretory Trafficking by the N-recognin UBR4/POE

Abstract

Most organisms possess circadian clocks that allow them to anticipate and accordingly respond to daily cycles in the natural and ecological environment. This endogenous timekeeping machinery is driven by numerous clock proteins, whose interaction generates daily rhythms in gene expression. At the core, ubiquitin ligase enzymes contribute immensely to the molecular clock by controlling the degradation of core clock proteins, which in turn serves to govern the speed and resetting properties of the central circadian clock. However, few studies have addressed their potential to regulate other cellular events within clock neurons beyond clock protein turnover. Here, I report that the ubiquitin ligase, UBR4/POE, strengthens the central pacemaker by facilitating neuropeptide trafficking in clock neurons and promoting network synchrony. Ubr4-deficient mice are resistant to jet lag and prone to constant light-induced arrhythmicity, whereas poe knockdown flies become arrhythmic under constant dark conditions. These behaviors are reflective of the reduced axonal trafficking of circadian neuropeptides induced by the loss of Ubr4/poe in clock neurons. In addition to impaired neuropeptide transport, the absence of Ubr4/poe also perturbs the expression of the core clock protein, PERIOD in both mouse and fly clock neurons. However, it appears that the in vivo behaviors are best explained by the neuropeptide transport deficit, which led me to pursue this phenotype further. The biosynthetic secretory pathway is responsible for the synthesis and trafficking of membrane and secreted proteins, including neuropeptides. Within this pathway, I found that Ubr4 ablation leads to altered Golgi morphology and impedes the export of secreted proteins from the Golgi apparatus by reducing the expression of Coronin 7, a protein essential for the budding of Golgi-derived transport vesicles. In summary, this work reveals a conserved and unexpected role of UBR4/POE in the vesicular trafficking of neuropeptides, a function that has important implications for circadian clock synchrony and circuit-level signal processing.

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Meeting ID: 856 0629 3500