New paper from Florey Lab - Pharmacological autophagy modulators induce unconventional LC3 lipidation

New paper from Florey Lab – Pharmacological autophagy modulators induce unconventional LC3 lipidation

Oliver Florey’s lab (The Babraham Institute, Cambridge) recently published their latest finding on non-canonical autophagy, a process that links autophagy to the degradation of external material. During non-canonical autophagy, the unconventional use of some autophagy proteins drives LC3 lipidation onto single-membrane compartments of the endolysosomal system. This pathway plays an important role in the immune system in the context of LC3-associated phagocytosis (LAP).

Modulating autophagy is an attractive therapeutic target for a range of diseases. Many autophagy modulating drugs have been identified that target lysosomes and inhibit autophagic flux. However, identification of these autophagy modulating drugs commonly relies on measuring LC3 lipidation as a read out. The Florey lab now raises important issues with the use of LC3 lipidation to specifically infer a role for canonical autophagy.

Using cell lines that are deficient for canonical autophagy and human tissue samples, they show that a range of clinically relevant drugs thought to inhibit autophagosome flux, including chloroquine and lidocaine, are able to promote LC3 lipidation to endolysosomal compartments. Thus showing these drugs can activate non-canonical autophagy in parallel to their known effects on canonical autophagy. Importantly, autophagy activators CCCP and amiodarone can also activate non-canonical autophagy independently of autophagosome formation.

This paper highlights the unexpected functions of autophagy modulators and demonstrate that activation of drug-induced non-canonical autophagy is common feature of drugs with lysosomotropic or ionophore properties. This finding emphasises the need for a better understanding of the functional consequences of endolysosomal LC3 lipidation and also raises important questions regarding the design and analysis of high-throughput screens for autophagy modulators.

Click here to view the paper published in Autophagy

Activation of noncanonical autophagy and endolysosomal LC3 lipidation by lysosomotropic and ionophore drugs in atg13−/− MEFs.