ER-autophagy screen published in Cell

Did you know that cells eat their own organelles? This is best known when damaged mitochondria are degraded by autophagy (aka mitophagy). Failure to perform mitophagy can lead to diseases such as Parkinson’s. But many other organelles are also degraded by autophagy. We have been studying autophagy of the endoplasmic reticulum (ER-phagy), which is much less understood than mitophagy. Engulfing a mitochondria in an autophagosome sounds pretty straightforward, but ends up being complicated. Now imagine needing to do that for one part of the ER network! A handful of direct ER-phagy receptors are known. But these receptors are always on the ER, so it was not clear what really initiates and controls ER-phagy. How does the cell know what part to engulf? What are the signals that turn this on and off? What happens when it goes wrong?

Superstars Amos Liang (postdoc) and Emily Lingeman (PhD student) tackled this question in a big way. Using a highly sensitive fluorescent reporter for ER-phagy, they used CRISPRi to ask what genes regulate ER-phagy. The first surprise was that intact mitochondrial oxidative phosphorylation is required to successfully initiate ER-phagy. This is odd because preventing oxidative phosphorylation actually initiates bulk autophagy. But the opposite is true for ER-phagy! The second big surprise was that a weird post-translational modification called UFMylation is required for ER-phagy. Lots of mechanistic work showed how UFMylation machinery is brought to the ER surface and what gets UFMylated during ER-phagy. There are some very interesting parallels to mitophagy, but using totally different machinery. Third, many of the genes involved in ER-phagy are involved in peripheral neuropathy in humans. Since their role in ER-phagy wasn’t previously known, it wasn’t understood how they were connected to cause human disease. This work suggests that failure to do ER-phagy links them all and leads to neurodegeneration. There’s a lot going on here, so read the paper to find out more.  Congrats to Amos and Emily!