BBS Faculty Member - Daniel Finley

Daniel Finley

Department of Cell Biology

Harvard Medical School
Building C1, Room 404
240 Longwood Avenue
Boston, MA 02115
Tel: 617-432-3492
Fax: 617-432-1144
Email: daniel_finley@hms.harvard.edu
Lab Members: 7 postdoctoral fellows, 1 graduate student, 1 research assistant
Visit my lab page here.



The lab is interested in the ubiquitin-proteasome pathway. There are several ongoing projects:

Usp14 is a proteasome-associated deubiquitinating enzyme. We study both the mammalian (USP14) and yeast (Ubp6) forms of the enzyme. USP14/Ubp6 is a powerful regulator of the proteasome. Ubp6 functions noncatalytically to strongly inhibit the degradation of ubiquitinated substrate proteins (Hanna et al 2006, 2007). While it inhibits degradation, Ubp6 deubiquitinates the target protein in a stepwise manner. Deubiquitination is highly selective for proteins that are modified by more than one ubiquitin chain (Lee et al 2016). With time, deubiquitination proceeds towards completion, and the substrate loses all but one of its ubiquitin chains, which can prevent degradation. With Randy King, we identified small-molecule inhibitors of Usp14, which penetrate cells and allow for enhanced degradation of many proteins, including toxic proteins involved in various diseases (Lee et al 2010). USP14 is activated ~1000-fold by the proteasome, and one current interest is to understand the mechanism of activation.

Another proteasome-associated factor is a ubiquitin ligase–Hul5. Deubiquitination of the substrate by Ubp6 is antagonized by Hul5 (Crosas et al 2006). Thus, ubiquitin chains are in a dynamic state on the proteasome, and chain dynamics regulate substrate selection by the proteasome. In the absence of Hul5 multiple substrates are degraded nonprocessively (i.e., fragments escape degradation). We are studying the mechanism of this effect.

The proteasome recognizes its substrates through attached ubiquitin moieties. We and our colleagues have identified to date six distinct receptors for ubiquitin that serve the proteasome, three that are specific integral subunits of the proteasome, and three that associate reversibly with the proteasome via ubiquitin-like domains (Shi et al 2016). Our genetic analysis indicates that additional ubiquitin receptors exist. We are trying to identify new receptors and to better understand why substrate recognition by the proteasome involves so many factors.

During terminal differentiation, the global protein complement is remodeled to a remarkable extent, as epitomized by erythrocytes, whose cytosol is ~98% globin. The erythroid proteome undergoes a rapid transition at the reticulocyte stage. We recently reported that UBE2O is a broad-spectrum ubiquitinating enzyme that globally remodels the erythroid proteome (Nguyen et al 2017). UBE2O recognizes substrates directly, targeting them to proteasomes for degradation. Thus, in reticulocytes, the induction of ubiquitinating factors may drive the transition from a complex to a simple proteome. Our goal in ongoing work is to understand the role of additional factors in late-stage differentiation of reticulocyte and other specialized cell types.



Last Update: 9/1/2017



Publications

For a complete listing of publications click here.

 


 

Lee et al. (2016) USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532: 398-401. PMID: 27074503

Shi Y et al. (2016) Rpn1 provides adjacent receptors sites for substrate binding and deubiquitination by the proteasome.
Science 351: aad9421. PMID: 26912900

Nguyen et al. (2017) UBE2O remodels the proteome during terminal erythroid differentiation.
Science 357: eaan0218. PMID: 28774900



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