An Autocrine Proliferation Repressor Regulates Dictyostelium discoideum Proliferation and Chemorepulsion Using the G Protein-Coupled Receptor GrlH

Abstract

In eukaryotic microbes, little is known about signals that inhibit the proliferation of the cells that secrete the signal, and little is known about signals (chemorepellents) that cause cells to move away from the source of the signal. Autocrine proliferation repressor protein A (AprA) is a protein secreted by the eukaryotic microbe Dictyostelium discoideum. AprA is a chemorepellent for and inhibits the proliferation of D. discoideum. We previously found that cells sense AprA using G proteins, suggesting the existence of a G protein-coupled AprA receptor. To identify the AprA receptor, we screened mutants lacking putative G protein-coupled receptors. We found that, compared to the wild-type strain, cells lacking putative receptor GrlH (grlH¯ cells) show rapid proliferation, do not have large numbers of cells moving away from the edges of colonies, are insensitive to AprA-induced proliferation inhibition and chemorepulsion, and have decreased AprA binding. Expression of GrlH in grlH¯ cells (grlH¯/grlHOE) rescues the phenotypes described above. These data indicate that AprA signaling may be mediated by GrlH in D. discoideum.

An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells

“…We previously observed that AprA binds to the G-protein–coupled receptor GrlH, requires GrlH and the G protein Gβ to inhibit proliferation and to induce chemorepulsion, and uses the G protein Gα8 to inhibit proliferation (Bakthavatsalam et al. , 2009; Phillips and Gomer, 2012; Tang et al. , 2018).…”

“…The beginning of the cAMP chemoattraction pathway involves a G protein–coupled receptor activating G proteins and Ras, and AprA uses the G protein–coupled receptor GrlH, and the G proteins Gα8 and Gβ (Phillips and Gomer, 2012; Tang et al. , 2018).…”

“…Compared to cAMP pulses, endogenous AprA gradients thus have a negligible temporal component. Cells sense AprA using the G-protein–coupled receptor GrlH to induce chemorepulsion (Tang et al. , 2018).…”

Extracellular signaling in Dictyostelium

“…Cells lacking AprA proliferate faster than wild type cells, whereas overexpression of AprA or the addition of recombinant AprA to cultures modestly slows, but does not stop, proliferation . In the extracellular environment, AprA forms a complex with a protein called CfaD (Choe et al, 2009, Tang et al, 2018. In addition to slowing proliferation, AprA acts as a chemorepellent for vegetative cells (Phillips and Gomer, 2012).…”

“…As with the chemoattractants cAMP and folic acid, AprA is sensed by a G protein coupled receptor called GrlH (Tang et al, 2018). As with chemoattraction to cAMP, AprA also induces Ras activation, and Ras activity is required for AprA-induced chemorepulsion (Rijal et al, 2018).…”