Cell Bio Faculty Candidate - Xin Gu

Catching transcription factors for proteasomal degradation: a dance with chromatin
Date
Jan 17, 2024, 12:00 pm1:00 pm

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Catching transcription factors for proteasomal degradation: a dance with chromatin

Cells use ubiquitin to mark proteins for proteasomal degradation. While the proteasome also eliminates proteins that are not ubiquitinated, how this occurs mechanistically is unclear. My postdoc work revealed that midnolin promotes the destruction of many nuclear proteins including transcription factors encoded by the immediate-early-genes. Diverse stimuli induce midnolin and its overexpression is sufficient to cause the degradation of its targets by a mechanism that does not require ubiquitination. Instead, midnolin associates with the proteasome via an a helix, employs its Catch domain to bind a region within substrates that can form a b strand, and uses a ubiquitin-like-domain to promote substrate destruction. Thus, midnolin contains three regions that function in concert to target a large set of nuclear proteins to the proteasome for degradation. Going forward, my lab’s initial efforts will be focusing on establishing this ubiquitination-independent degradation pathway from three angles: first, the biochemical, structural and cell biological mechanisms; second, the organismal consequences if this pathway is perturbed; third, the potential to hijack this pathway to target transcription factors of interest.

 

Contact
Jared Toettcher