BMC molecular and cell biology · 2026
Genetic suppressor of autophagy defects in huntingtin null cells identified using a mutagenesis screen in Dictyostelium discoideum.
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Cuoco Lauren, Gill Shelbi E, Francois Luc, Souders Sarah, DeMasi Caroline, Moore Jeffrey R, Chain Frédéric J J
Аннотация
BACKGROUND: Huntingtin (HTT) is an important gene for cellular processes such as autophagy, and its loss leads to neurodegenerative disease phenotypes. In Dictyostelium discoideum, HTT-null (htt-) cells exhibit impaired basal autophagy and fail to develop in the presence of ammonium chloride.
RESULTS: Here we conducted a mutagenesis screen on htt- cells to identify potential genetic suppressors of the htt- phenotype. A mutant strain was isolated that counteracts many of the hallmark defects engendered with htt loss. This mutant, htt-;supX, rescues the growth, cargo degradation defects, developmental timing, and autophagic flux of htt- cells under ammonium chloride stress, representing a partial rescue of the htt- phenotype. Whole-genome sequencing revealed four mutations in the mutant strain affecting genes involved in vesicle trafficking, signal transduction, metal ion regulation, and fatty acid elongation. Transcriptome sequencing further identified 208 differentially expressed genes in the mutant strain, including genes whose expression was returned to wild-type levels, suggesting a potential mechanism by which htt-;supX mediates phenotypic recovery. Among these, five genes have known autophagy-related functions and may be implicated in pathways such as Rab GTPase regulation and SNARE-mediated vesicle fusion.
CONCLUSIONS: Our study highlights the ability of second-site mutations to restore autophagic function in the absence of HTT and identifies candidate genes and pathways for further investigation into Huntington's Disease models and autophagy modulation.
RESULTS: Here we conducted a mutagenesis screen on htt- cells to identify potential genetic suppressors of the htt- phenotype. A mutant strain was isolated that counteracts many of the hallmark defects engendered with htt loss. This mutant, htt-;supX, rescues the growth, cargo degradation defects, developmental timing, and autophagic flux of htt- cells under ammonium chloride stress, representing a partial rescue of the htt- phenotype. Whole-genome sequencing revealed four mutations in the mutant strain affecting genes involved in vesicle trafficking, signal transduction, metal ion regulation, and fatty acid elongation. Transcriptome sequencing further identified 208 differentially expressed genes in the mutant strain, including genes whose expression was returned to wild-type levels, suggesting a potential mechanism by which htt-;supX mediates phenotypic recovery. Among these, five genes have known autophagy-related functions and may be implicated in pathways such as Rab GTPase regulation and SNARE-mediated vesicle fusion.
CONCLUSIONS: Our study highlights the ability of second-site mutations to restore autophagic function in the absence of HTT and identifies candidate genes and pathways for further investigation into Huntington's Disease models and autophagy modulation.