Like some people, cells eat when they are under pressure—but they consume parts of themselves. Tang et al. show that a multi-function protein helps control this form of cannibalism.

Cells often respond to hunger or stress by digesting some of their contents. The process, known as autophagy, helps free nutrients and clean up cytoplasmic trash such as worn-out organelles and misshapen proteins. Tang et al. discovered a link between this form of cellular recycling and the protein HMGB1. Inside the nucleus, HMGB1 bends DNA so that transcription factors can gain access to important regulatory genes. HMGB1 has an extracellular role, too. Dying cells shed the protein to trigger inflammation.

The researchers wanted to determine whether HMGB1 also has a function in the cytosol. They found that starving cells transfer HMGB1 from the nucleus to the cytosol. Once there, HMGB1 induces autophagy—self-eating slowed in cells lacking the protein. HMGB1 flips a key autophagy switch, separating the proteins Beclin1 and Bcl-2, which normally cling to each other to suppress the pathway.

Stressed-out cells hike their production of reactive oxygen species, which change HMGB1's behavior, Tang et al. discovered. Oxidation of a particular cysteine in HMGB1 springs the protein from the nucleus. Oxidation of two other cysteines enables HMGB1 to bind Beclin1 and separate it from Bcl-2. This suggests that blocking HMGB1 could benefit cancer patients, since tumor cells often rev up autophagy to withstand chemotherapy, immunotherapy, and radiation treatment.

et al
J. Cell Biol.