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Hirschi, S.

Publications and source records attributed to Hirschi, S..

2 recordsLinked to original sources
bioRxiv2026

Structural and functional basis of the non-canonical human Dicer-tRNA complex

Human Dicer (hDicer) is a key enzyme in the RNA interference (RNAi) pathway that generates [~]21-22 nt micro-RNA (miRNAs) and small interfering RNAs (siRNAs). We have previously shown that hDicer also generates tRNA-derived small RNAs (tsRNAs), which mediate nuclear gene silencing and regulate hundreds of disease-associated genes. As powerful and evolutionarily conserved cellular regulators, tsRNAs emerged as an important class of small RNAs. Therefore, it is essential to understand their biogenesis. However, the molecular and structural basis of tRNA cleavage by hDicer, as well as the role of chemical modifications such as 5-methylcytosine (m5C), in this process, remain unknown. Here, we present the first structural insights into hDicer in complex with tRNA, obtained by cryo-electron microscopy (cryo-EM), selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) and molecular dynamics (MD) simulations. Our results reveal that tRNAs adopt alternative conformations that are recognized and processed by hDicer. Furthermore, we show that tRNA cleavage by hDicer is facilitated by the m5C modification deposited by Nop2/SUN RNA methyltransferase 2 (NSUN2). Collectively, our findings redefine tRNAs as bona fide hDicer substrates and uncover a modification-dependent biogenetic pathway that reshapes the current understanding of the origins and regulation of human small RNAs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/744379v1_ufig1.gif" ALT="Figure 1000"> View larger version (24K): org.highwire.dtl.DTLVardef@14a8682org.highwire.dtl.DTLVardef@1c4d0daorg.highwire.dtl.DTLVardef@6bc433org.highwire.dtl.DTLVardef@11e27e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗
bioRxiv2026

Plasmodium berghei liver stages establish a damage-mimicking vacuole to hijack host ER membrane contact site machinery for lipid uptake

Plasmodium liver stage parasites undergo massive intracellular replication and therefore require extensive acquisition of host-derived lipids. How parasites coordinate lipid supply at the host-parasite interface, however, remains poorly understood. Here, we show that the Plasmodium berghei parasitophorous vacuole membrane (PVM) selectively mimics features of damaged endolysosomal membranes, including dynamic LC3-positive membrane tubules and PI4K2A-dependent PI(4)P accumulation, while lacking canonical damage markers including ESCRT components and galectins. This damage-mimicking membrane state drives OSBP recruitment and is associated with formation of VAPA/B-positive ER-PVM membrane contact sites. Disruption of VAPA/B or OSBP impaired PVM integrity and parasite survival, while OSBP depletion reduced cholesterol accumulation at the PVM. Together, our findings suggest that liver stage parasites exploit host lysosome repair-like pathways to redirect host lipids toward parasite growth and intracellular survival. These results redefine the PVM as an active metabolic interface that enables host lipid acquisition rather than merely serving as a protective barrier.

microbiology↗