Abstract
Retrograde transport is a critical mechanism for recycling certain membrane cargo. Following endocytosis from the plasma membrane, retrograde cargo is moved from early endosomes to Golgi followed by transport (recycling) back to the plasma membrane. The complete molecular and cellular mechanisms of retrograde transport remain unclear. The small GTPase RAB-6.2 mediates the retrograde recycling of the AMPA-type glutamate receptor (AMPAR) subunit GLR-1 in C. elegans neurons. Here we show that RAB-6.2 and a close paralog, RAB-6.1, together regulate retrograde transport in both neurons and non-neuronal tissue. Mutants for rab-6.1 or rab-6.2 fail to recycle GLR-1 receptors, resulting in GLR-1 turnover and behavioral defects indicative of diminished GLR-1 function. Loss of both rab-6.1 and rab-6.2 results in an additive effect on GLR-1 retrograde recycling, indicating that these two C. elegans Rab6 isoforms have overlapping functions. MIG-14 (Wntless) protein, which undergoes retrograde recycling, undergoes a similar degradation in intestinal epithelia in both rab-6.1 and rab-6.2 mutants, suggesting a broader role for these proteins in retrograde transport. Surprisingly, MIG-14 is localized to separate, spatially segregated endosomal compartments in rab-6.1 mutants compared to rab-6.2 mutants. Our results indicate that RAB-6.1 and RAB-6.2 have partially redundant functions in overall retrograde transport, but also have their own unique cellular- and subcellular functions.
Highlights
Cells direct their subcellular organization through the regulated trafficking of lipids and membrane-bound proteins to specific membrane compartments
We found that C. elegans RAB-6.1 contains valine at position 63, whereas RAB-6.2 contains isoleucine
We found that C. elegans RAB-6.1 contains threonine and serine at positions 106 and 139, respectively, whereas RAB-6.2 contains serine and threonine at those positions
Summary
Cells direct their subcellular organization through the regulated trafficking of lipids and membrane-bound proteins to specific membrane compartments. Membrane trafficking in turn is organized by Rab proteins, which are members of the Ras small GTPase superfamily [1,2]. How multiple Rabs work together to regulate specific membrane trafficking pathways remains an open question. Individual Rab family members appear to direct traffic between membranes of specific subcellular structures, and the large number of Rab family members reflects the numerous and diverse transport pathways that exist within cells. An understanding of the dedicated function of each Rab family member should shed light on the strategy by which cells organize their membrane compartments
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