Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jul 20;30(7):739-752.e8.
doi: 10.1016/j.chembiol.2023.05.010. Epub 2023 Jun 14.

ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation

Affiliations
Free article

ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation

Rui Sun et al. Cell Chem Biol. .
Free article

Abstract

Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention, but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP-signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins. As a proof-of-concept, we targeted the immune checkpoint protein, programmed death ligand 1 (PD-L1), a prominent cancer therapeutic target, with a bispecific RSPO2 chimera, R2PD1. The R2PD1 chimeric protein binds to PD-L1 and at picomolar concentration induces its lysosomal degradation. In three melanoma cell lines, R2PD1 induced between 50 and 90% PD-L1 protein degradation. PD-L1 degradation was strictly dependent on ZNRF3/RNF43. Moreover, R2PD1 reactivates cytotoxic T cells and inhibits tumor cell proliferation more potently than Atezolizumab. We suggest that signaling-disabled ROTACs represent a paradigm to target cell surface proteins for degradation in a range of applications.

Keywords: LYTAC; PD-L1; PROTAC; R-spondin; RNF43; ZNRF3; lysosome; protein degradation; transmembrane E3 ligase.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare the following competing financial interest(s): R.S., C.N., and the DKFZ have filed a patent application (International Application No. EP 22 194 882.1) related to this study.

Publication types

MeSH terms

LinkOut - more resources