How cells “sense” protein damage and controls aggregation of damaged polypeptides
Michael Sherman1
1Ariel University, sherma1@ariel.ac.il
Protein abnormalities in cells is the cause of major pathologies, and a number of adaptive responses have evolved to relieve toxicity of misfolded polypeptides. To trigger these responses cells must detect the buildup of aberrant proteins. We uncovered that the “sensor” of damaged polypeptides is molecular chaperone Hsp70, which associates with a scaffold protein Bag3. When damage proteins bind to Hsp70, Bag3 transmits this signal to the Hippo pathway (protein kinase LATS1), stress kinases and other important signaling pathways to trigger protective responses. Counterintuitively, it appears that aggregation of damaged proteins, which could cause cell toxicity is not a spontaneous process, but a tightly controlled response regulated by the Hsp70-Bag3 and the downstream LATS1 axis. Using super-resolution microscopy, in collaboration with a lab at MIT, we established that the regulated step is emergence and growth of abnormal protein clusters containing just few molecules. Quantitative analysis of distribution of protein clusters uncovered that in response to accumulation of damaged proteins, the “stickiness” of abnormal polypeptides (their interaction force) increases to promote formation of clusters. Knocking down Bag3 prevented the enhancement of the “stickiness” without affecting the levels of abnormal proteins, while suppression of LATS1 had opposite effects. The Hsp70-Bag3-LATS1 therefore functions as an important signaling node that senses protein damage and triggers multiple pathways that control cell physiology, including activation of protein aggregation.Enter the abstract annotation ONLY here