Biology subjects

Yates, R. M.

Publications and source records attributed to Yates, R. M..

3 recordsLinked to original sources

bioRxiv2025

The pore-forming protein APOL7C ruptures Leishmania major-containing parasitophorous vacuoles in dendritic cells to promote IL-12 production and the induction of T helper type 1 immunity

Classical dendritic cells (cDCs) are required for the efficient priming of T helper type 1 (Th1) immunity against Leishmania major infections in mice. They do so by producing large quantities of IL-12 in response to L. major infection. IL-12 in turn supports the generation of protective CD4+ Th1 cells. However, the mechanism(s) by which L. major instigates robust IL-12 production by cDCs has not been addressed. Here we show that expression of a pore-forming protein called APOL7C is induced in cDCs by L. major infection. APOL7C is expressed in the cytosol of host cells and, remarkably, upon infection is recruited to L. major parasitophorous vacuoles (PVs) where it induces PV rupture. PV rupture leads to the exposure of L. major-derived pathogen-associated molecular patterns (PAMPs) to cytosolic pattern recognition receptors (PRRs). Cytosolic PRR signaling then drives IL-12 production by cDCs. Consequently, L. major challenge of APOL7C-deficient mice results in reduced numbers of IL-12 producing cDCs as well as a diminished Th1 response. In sum, our data indicate the presence of pore-forming proteins in the cytosol of cDCs that interfere with the intracellular niche of Leishmania to modulate immunity to these parasites.

cell biology↗

bioRxiv2025

Probing the activity of cysteine cathepsins in inflammatory bowel diseases

Cathepsin S is a cysteine protease that has been implicated in inflammatory bowel diseases (IBD) for its ability to promote visceral pain. Given its pro-inflammatory roles, we hypothesized that cathepsin S would drive other symptoms associated with IBD. Using activity-based probes, we investigated cysteine cathepsin activation in human and murine colitis. We observed a significant increase in fecal cathepsin S in patients with ulcerative colitis compared to healthy controls, while cathepsin S in mucosal biopsies was unchanged. Mice with experimental colitis exhibited a modest increase in mucosal activity of both cathepsin S and X compared to naive mice. Luminal secretion of cathepsin S was dramatically increased upon colitis induction, although differences between mouse colonies were observed. To investigate the contribution of cathepsin S and cathepsin X to colitis, we induced colitis in cathepsin-deficient mice. Cathepsin X-deficient mice exhibited no clear differences in disease indicators compared to wild-type mice. While cathepsin S-deficient mice exhibited less rectal bleeding, less splenomegaly and marginally improved histological scores, weight loss, diarrhea, colon shortening, and myeloperoxidase activity were not significantly different from wild-type mice. To determine whether pharmacologic inhibition of cathepsin S activity would ameliorate symptoms of colitis, a reversible inhibitor LY3000328 was administered to mice at the initiation of colitis. LY3000328 provoked a clear upregulation of cathepsin S and L activity in the mucosa, most likely through a compensatory mechanism. This increase in protease activity was associated with exacerbated histological scores and splenomegaly. Collectively, these results suggest that cathepsin S, but not cathepsin X, may contribute to some of the symptoms of experimental colitis. While cathepsin S has potential to be a therapeutic target in colitis, improved strategies to sustain its inhibition are required in future.

pathology↗

bioRxiv2023

The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells

Type I conventional dendritic cells (cDC1s) are essential for the generation of protective cytotoxic T lymphocyte (CTL) responses against many types of viruses and tumours. They do so by internalizing antigens from virally infected or tumour cells and presenting them to CD8+ T cells in a process known as cross-presentation (XP). Despite the obvious biological importance of XP, the molecular mechanism(s) driving this process remain unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein 7C (APOL7C) is upregulated in response to innate immune stimuli and is recruited to phagosomes. Strikingly, the association of APOL7C with phagosomes leads to phagosomal rupture, which in turn allows for the escape of engulfed protein antigens to the cytosol where they can be processed via the endogenous major histocompatibility complex (MHC) class I antigen processing pathway. We show that APOL7C recruitment to phagosomes is voltage-dependent and occurs in response to NADPH oxidase-induced depolarization of the phagosomal membrane. Our data indicate the presence of dedicated pore-forming apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDC1s to facilitate MHC class I presentation of exogenous antigen and to regulate adaptive immunity.

cell biology↗