The membrane protein, stomatin, was first discovered in human erythrocytes and derives its name from the observation that stomatin protein levels are reduced in patients suffering from the hereditary cation transport disease, stomatocytosis. Recent work from the Chalfie lab suggests that stomatin interacts directly with the DEG/ENaC class of sodium channels to regulate cation transport.
unc-24 encodes a novel stomatin-like protein (SLP) that includes an N-terminal stomatin domain as well as a C-terminal region resembling the non-specific Lipid Transfer Protein (nsLTP). Sedensky et al., (2001) have shown that UNC-24 is required for the cell surface localization and stability of another SLP, UNC-1; in
unc-24 mutants, UNC-1 protein levels are substantially reduced and largely restricted to perinuclear dots in the vicinity of the Golgi apparatus. We have now shown that a transgene encoding GFP-tagged UNC-24 protein under the control of the
unc-24 promoter is widely expressed in C. elegans neurons and is sufficient to rescue the
unc-24 forward movement defect. Interestingly, hSLP-1, the human homologue of UNC-24, is also highly expressed in the nervous system. UNC-24::GFP is concentrated in bright juxtanuclear puncta; however, weaker yet detectable localization to neuronal processes is evident in some cells (e.g. touch neurons) (see Bianchi et al., this meeting). These results suggest that UNC-24 may function in the Golgi compartment for processing or sorting of UNC-1. We are currently utilizing affinity-purified UNC-24 polyclonal antibodies to establish the subcellular localization of native UNC-24. Our genetic data suggest that UNC-24 interacts with UNC-8, a DEG/ENaC channel protein expressed in ventral cord motor neurons. Although
unc-8 loss-of-function (lf) mutants show nearly normal locomotion, rare
unc-8(d) mutants are severely uncoordinated due to constitutive UNC-8 activity.
unc-8(lf) mutants suppress the movement defect of
unc-24(lf) mutants. Rajaram et al., (1999) have previously shown that
unc-8(lf) also suppresses the forward locomotory defect of
unc-1(lf) mutants. We suggest that UNC-24 functions as a negative regulator of the UNC-8 channel possibly through an interaction with UNC-1. Current experiments are designed to delineate the mechanism by which UNC-24 regulates UNC-8 and to identify the neuronal compartments crucial to this locomotory pathway.