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Publications of the Week

Coxsackievirus Infection Induces a Non-Canonical Autophagy Independent of the ULK and PI3K Complexes

By November 16, 2020November 20th, 2020No Comments

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This week we profile a recent publication in Scientific Reports from Yasir Mohamud (pictured)
in the laboratory of Dr. Honglin Luo at the Centre for Heart Lung Innovation at St. Paul’s Hospital.

Can you provide a brief overview of your lab’s current research focus?

The Luo Laboratory studies mechanisms of viral pathogenesis with a particular focus on heart disease and neurodegeneration while also investigating strategies to leverage oncolytic virus for cancer therapy. As common human pathogens, enteroviruses (EVs) are responsible for ~1 billion global infections annually, with severe health outcomes manifesting in the vulnerable populations including infants, the elderly, and the immune-compromised. Recent evidence shows that EVs can hijack the host autophagy pathway for effective viral replication leading to cardiovascular and neurological disorders; however, the underlying mechanisms remain poorly defined. The focus of this project is to elucidate the molecular mechanism by which EVs subvert the host autophagy pathway.

What is the significance of the findings in this publication?

The recent publication by Mohamud et al. uncovers the surprising molecular insight that coxsackievirus B3 (CVB3, an EV) initiates autophagy independent of previously established canonical factors. Using established culture models and CRISPR-Cas9 based gene editing, the authors exclude the requirement for several canonical autophagy factors in the initiation of CVB3-induced autophagy.  The study identified the serine-threonine kinase ULK1 (ATG1) as a novel target of viral protease 3C and the PI4P lipid-kinase, PI4KIIIβ, as an important regulator of CVB3-induced non-canonical autophagy. These insights clarify our understanding of viral pathogenesis via the disruption of autophagy and provide novel molecular targets to combat an emerging global threat.

What are the next steps for this research?

The ongoing/future aims of this project are to (1) investigate the mechanism and outcome of impaired function of lysosome (an organelle that contains digestive enzymes required for autophagy-mediated recycling); and (2) develop anti-viral inhibitors based on the mechanism identified in cells that prevent EV-mediated disruption of autophagy.

This work was funded by:

This research is supported by the Canadian Institutes of Health Research (PJT-173318 and PJT 159546) to Honglin Luo (Senior author). The first author (Yasir Mohamud) is supported by four-year PhD fellowship from University of British Columbia and Doctoral Fellowship from ALS Canada-Brain Canada.

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