School of Infection & Immunity

Dr Mathieu Cayla

Title: Signalling and regulation of autophagy-related pathways in T. brucei

Synopsis: The protozoan parasite Trypanosoma brucei relies on exquisite environmental sensing to drive differentiation and host adaptation throughout its lifecycle. In the mammalian host, slender bloodstream forms sense parasite density via a quorum-sensing (QS) mechanism, triggering differentiation into quiescent, transmission-adapted stumpy forms. Our laboratory investigates the organellar and signalling networks that coordinate this lifecycle progression, with a primary focus on the regulatory protein kinases governing autophagy, complemented by the study of an unconventional lysosome exocytosis pathway.

Although autophagy is essential for kinetoplastid differentiation, they apparently lack canonical initiation complexes and protein kinases (e.g., ATG1/ULK1). Our lab, primarily uses proximity labelling to map the molecular components of autophagy that have not yet been identified in Kinetoplastids. We defined the proximity proteome of canonical autophagy markers such as ATG8 and the early autophagic markers ATG12/16 in T. brucei. We demonstrated that autophagy is activated via unexpected short, successive waves rather than continuously. We are now in the process of validating the identification of specific protein kinases controlling distinct steps of autophagosome biogenesis, including the elusive ATG1/ULK1 complex.

In tandem, we are investigating how organellar trafficking contributes to the extracellular signals driving this same QS pathway. Bloodstream T. brucei secretes peptidases that generate signalling oligopeptides and facilitate differentiation and possibly tissue invasion, yet their secretory route has remained unknown. Recent studies have identified an unconventional, autophagy-dependent secretory pathway called lysosome exocytosis, which is implicated in plasma membrane repair, the secretion of undegraded components targeted to the lysosome, and the secretion of peptidases/hydrolases directly into the extracellular matrix. We revealed that secreted peptidases are trafficking through the lysosome and are secreted via a calcium- dependent pathway reminiscent of lysosomal exocytosis. We are now in the process of validating the molecular components, as identified again using proximity labelling, involved in such secretory pathway.

Together, these complementary lines of research investigate how T. brucei integrates non-canonical kinase networks with specialised organellar dynamics to balance autophagic degradation and lysosome secretion during environmental adaptation, differentiation, and host persistence.

Bio: Mathieu is an MRC CDA Fellow and Group Leader at the University of York. His laboratory investigates the molecular mechanisms that enable trypanosome parasites to sense, differentiate, and adapt to their environment. Mathieu completed his PhD at the Institut Pasteur Paris under the supervision of Dr. Najma Rachidi in the laboratory of Dr. Gerald Spaeth, investigating the role of MAP kinases during amastigogenesis in Leishmania parasites. In 2015, he joined Prof. Keith Matthews’ lab at the University of Edinburgh as a Marie Curie Fellow to study the role of T. brucei protein kinases in regulating quorum-sensing differentiation in the mammalian bloodstream. In 2022, he established his independent research group at the University of York.

First published: 8 September 2026

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