Researchers provide critical insights into the molecular mechanisms underlying lysophagy



Autophagy is an autolysis process that cells use to remove unnecessary or damaged components. There are several forms of autophagy, including autophagy, which is a collective hydrolysis system used to target substances in the cytosol of a cell to organelles called lysosomes for enzymatic breakdown. However, even the lysosomes themselves sometimes need to be degraded. Recently, Osaka University researchers examined the specific molecular details of how damaged lysosomes are selected and characterized for disposal.

In a recent article published in cell reportsThe team described a process called lysophagy, the specific form of selective autophagy responsible for removing damaged lysosomes. Previous studies have shown that substances such as toxins, fats, cholesterol or urate crystals can rupture lysosomes. In addition to organelle dysfunction, this damage can also lead to oxidative stress and inflammation that may lead to disease progression. Therefore, the cell uses lysophagy to handle this. However, the mechanisms that control how cells are able to recognize and target damaged lysosomes for lysis are not fully understood.

We know from previous investigations that lysosomes can be tagged by a specific enzyme, SCFFBXO27 Through a process called polyubiquitination. Expression of SCFFBXO27 It was only observed in brain and muscle tissue, so we hypothesized that another ubiquitous enzyme should be present for lysophagy in other cell types.”


Hirofumi Teranishi, one of the lead authors

The team used polystyrene beads coated with a reagent that can cause internal damage and then spread everywhere. They then isolated the granules through centrifugation and used a method called mass spectrometry to identify the proteins associated with them, eventually narrowing the list down to 123 proteins.

“With the help of molecular techniques where we can knock down the expression of these different proteins, we have found that proteins called CUL4A, DDB1 and WDFY1 form a complex that responds to lysosomal damage,” explains Maho Hamasaki, senior author of the study.

Further characterization indicated that this compound acts preferentially during lysophagy and facilitates the addition of ubiquitin molecules. The WDFY1 protein is needed to specifically recognize damaged particles.

“We next wondered what part of the lysosome this protein complex recognized,” Teranishi says. “Many lysosomal proteins were examined, until we found LAMP2 to be the ubiquitous protein by the CUL4A complex.”

The team also found that the presence of LAMP2 and its interaction with WDFY1 are essential for initiating lysophagy. Overall, these results provide critical insights into the molecular mechanisms that are central to lysophagy. This may also help fight diseases in which this process is disorganized. In the future, the researchers plan to determine in more precise detail how the CUL4A complex recognizes LAMP2.

source:

Journal reference:

Teranishi, H.; et al. (2022) Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in lysophagy initiation. Cell reports. doi.org/10.1016/j.celrep.2022.111349.



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