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• W4301398519 abstract "Abstract Malaria parasites uniquely depend on protein secretion for their obligate intracellular lifestyle but approaches for dissecting Plasmodium secreted protein functions are limited. We report knockER, a novel DiCre-mediated knock-sideways approach to sequester secreted proteins in the ER by inducible fusion with a KDEL ER-retrieval sequence. We show conditional ER sequestration of diverse proteins is not generally toxic, enabling loss-of-function studies. Taking advantage of the unique ability to redistribute secreted proteins from their terminal destination to the ER, we employed knockER to separate HSP101 function in protein export at the parasite vacuole from a recently proposed role in cargo recognition at the ER. Strikingly, while KDEL-fusion produced similar ER retrieval of both HSP101 and the translocon adaptor PTEX150, parasite growth and effector export were unaffected by HSP101 retention while ER retrieval of PTEX150 produced a lethal defect, indicating vacuolar HSP101 levels are uniquely maintained in excess. Moreover, vacuole depletion of HSP101 hypersensitized parasites to a destabilization tag that inhibits HSP101-PTEX complex formation but not to translational knockdown of the entire HSP101 pool, revealing vacuole-localized function does not fully account for HSP101 contribution to parasite fitness. These findings imply an important role for HSP101 in the ER distinct from the PTEX complex, suggesting a link between events that designate proteins for export during secretory pathway entry and their ultimate translocation into the host cell by PTEX. Collectively, our results establish knockER as a novel tool for dissecting secreted protein function with sub-compartmental resolution that should be widely amenable to genetically tractable eukaryotes. Significance Erythrocyte remodeling by Plasmodium exported proteins is central to parasite survival and Malaria pathology. Effector proteins are transported from the parasite vacuole into the erythrocyte through the PTEX translocon, a process powered by the AAA+ chaperone HSP101. Using a novel approach to conditionally sequester secreted proteins in the ER (knockER), we provide evidence for a distinct HSP101 activity in the ER upstream of the effector translocation site at the assembled PTEX complex. Importantly, our results support a model where exported cargo is identified early in the secretory pathway, possibly linking proteolytic maturation in the ER that licenses exported proteins to recognition by PTEX. The knockER strategy is broadly applicable to functional dissection of proteins that traverse the eukaryotic secretory pathway." @default.
• W4301398519 created "2022-10-05" @default.
• W4301398519 creator A5009669850 @default.
• W4301398519 creator A5034932175 @default.
• W4301398519 creator A5048881750 @default.
• W4301398519 creator A5053059070 @default.
• W4301398519 date "2022-10-03" @default.
• W4301398519 modified "2023-10-15" @default.
• W4301398519 title "Knock-sideways by inducible ER retrieval reveals a novel extra-vacuolar function for<i>Plasmodium</i>PTEX component HSP101" @default.
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