BiDAC-dependent degradation of plasma membrane proteins by the endolysosomal system

Sammy Villa, Qumber Jafri, Julia R. Lazzari-Dean, Manjot Sangha, Niclas Olsson, Austin E. Y. T. Lefebvre, Mark E. Fitzgerald, Katrina Jackson, Zhenghao Chen, Brian Y. Feng, Aaron H. Nile, David Stokoe and Kirill Bersuker ()
Additional contact information
Sammy Villa: Calico Life Sciences LLC
Qumber Jafri: Calico Life Sciences LLC
Julia R. Lazzari-Dean: Calico Life Sciences LLC
Manjot Sangha: Calico Life Sciences LLC
Niclas Olsson: Calico Life Sciences LLC
Austin E. Y. T. Lefebvre: Calico Life Sciences LLC
Mark E. Fitzgerald: C4 Therapeutics Inc.
Katrina Jackson: C4 Therapeutics Inc.
Zhenghao Chen: Calico Life Sciences LLC
Brian Y. Feng: Calico Life Sciences LLC
Aaron H. Nile: Calico Life Sciences LLC
David Stokoe: Calico Life Sciences LLC
Kirill Bersuker: Calico Life Sciences LLC

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The discovery of bifunctional degradation activating compounds (BiDACs) has led to the development of a new class of drugs that promote the clearance of their protein targets. BiDAC-induced ubiquitination is generally believed to direct cytosolic and nuclear proteins to proteolytic destruction by proteasomes. However, pathways that govern the degradation of other classes of BiDAC targets, such as integral membrane and intraorganellar proteins, have not been investigated in depth. In this study we use morphological profiling and CRISPR/Cas9 genetic screens to investigate the mechanisms by which BiDACs induce the degradation of plasma membrane receptor tyrosine kinases (RTKs) EGFR and Her2. We find that BiDAC-dependent ubiquitination triggers the trafficking of RTKs from the plasma membrane to lysosomes for degradation. Notably, functional proteasomes are required for endocytosis of RTKs upstream of the lysosome. Additionally, our screen uncovers a non-canonical function of the lysosome-associated arginine/lysine transporter PQLC2 in EGFR degradation. Our data show that BiDACs can target proteins to proteolytic machinery other than the proteasome and motivate further investigation of mechanisms that govern the degradation of diverse classes of BiDAC targets.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59627-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59627-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59627-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().