GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.

Authors

Angélica Hollunder Klippel, Corryn Newman-Boulle, Grant Reed, Dule Dule, Saanya Kedia, Martin T Kelty, Wai Pang Chan, Han-Wei Shih, Alexander R Paredez

Published in

PLoS pathogens. Volume 22. Issue 10. Pages e1014624. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Autophagy is a conserved catabolic process essential for cellular homeostasis and adaptation to nutrient stress. The protozoan parasite Giardia lamblia lacks most canonical autophagy-related (ATG) genes, including the hallmark ATG8, raising longstanding questions about whether this deeply divergent parasite can perform autophagy. Here, we identify an ATG8-independent autophagy-like pathway in Giardia regulated by GlRac, the parasite's sole Rho family GTPase. GlRac-positive double-membrane compartments are induced by encystation and nutrient depletion, and their abundance rapidly declines following amino acid replenishment but is unaffected by glucose, indicating amino acid-specific regulation. Giardia Target of Rapamycin (GTOR) levels decrease during nutrient depletion, and GTOR knockdown increases compartment abundance, identifying GTOR as a negative regulator of compartment formation and linking this pathway to nutrient sensing. Time-lapse microscopy revealed that these compartments form through linear and cup-shaped intermediates before becoming spherical and are subsequently cleared upon nutrient replenishment. Of nine putative ATG orthologs examined, none localized as specifically as GlRac to these structures, supporting the existence of a highly divergent pathway. Nevertheless, the compartments exhibit multiple conserved autophagy-associated features, including double-membrane morphology, actin recruitment, acidification, and cysteine protease activity. Pharmacological inhibition of cysteine proteases with E-64d or blocking V-ATPase-mediated acidification with concanamycin A promotes compartment accumulation, consistent with continuous degradative turnover. GlRac regulates compartment biogenesis bidirectionally: constitutive activation increases compartment abundance and size, whereas knockdown reduces them. Finally, quinacrine, an FDA-approved antigiardial drug that accumulates in acidic organelles, perturbs GlRac-positive compartments, consistent with its reported effects on autophagy in other eukaryotes, raising the possibility that this pathway contributes to parasite fitness. Together, these findings establish GlRac as a central regulator of an ATG8-independent autophagy-like pathway in Giardia and demonstrate that this parasite retains key structural, regulatory, and degradation-associated features of autophagy despite the apparent absence of most canonical ATG machinery.

PMID:
42837424
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.