SEL-2, theC. elegansneurobeachin/LRBA homolog, is a negative regulator oflin-12/Notchactivity and affects endosomal traffic in polarized epithelial cells

Abstract

The vulval precursor cells (VPCs) of Caenorhabditis elegans are polarized epithelial cells that adopt a precise pattern of fates through regulated activity of basolateral LET-23/EGF receptor and apical LIN-12/Notch. During VPC patterning, there is reciprocal modulation of endocytosis and trafficking of both LET-23 and LIN-12. We identified sel-2 as a negative regulator of lin-12/Notch activity in the VPCs, and found that SEL-2 is the homolog of two closely related human proteins, neurobeachin (also known as BCL8B) and LPS-responsive, beige-like anchor protein (LRBA). SEL-2, neurobeachin and LRBA belong to a distinct subfamily of BEACH-WD40 domain-containing proteins. Loss of sel-2 activity leads to basolateral mislocalization and increased accumulation of LIN-12 in VPCs in which LET-23 is not active, and to impaired downregulation of basolateral LET-23 in VPCs in which LIN-12 is active. Downregulation of apical LIN-12 in the VPC in which LET-23 is active is not affected. In addition, in sel-2 mutants, the polarized cells of the intestinal epithelium display an aberrant accumulation of the lipophilic dye FM4-64 when the dye is presented to the basolateral surface. Our observations indicate that SEL-2/neurobeachin/LRBA is involved in endosomal traffic and may be involved in efficient delivery of cell surface proteins to the lysosome. Our results also suggest that sel-2 activity may contribute to the appropriate steady-state level of LIN-12 or to trafficking events that affect receptor activation.

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“…Most commonly, endocytosis followed by receptor degradation terminates signaling. However, endocytosis can also prolong the duration of signaling (Jullien and Gurdon, 2005) or influence its subcellular location (de Souza et al, 2007;Howe and Mobley, 2005). Receptors may also signal through different downstream pathways localized to specialized endosomal compartments (Di Guglielmo et al, 2003;Miaczynska et al, 2004;Teis et al, 2006).…”

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