Degrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol. Using , we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate proteasomal degradation through the ERAD system. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation in budding yeast and mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and builds toward therapeutic approaches that exploit the highly-conserved ERAD system.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326120 | PMC |
http://dx.doi.org/10.1101/2023.06.21.546000 | DOI Listing |
Cell Rep
December 2024
Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea; AUTOTAC Bio, Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul 03077, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address:
The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway.
View Article and Find Full Text PDFElife
November 2024
Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, United States.
Degrons are minimal protein features that are sufficient to target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, all of the identified degrons only function within the cytosol.
View Article and Find Full Text PDFMethods Enzymol
November 2024
Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan; Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan. Electronic address:
Precise protein localization is essential for normal cellular functions. However, recent studies have revealed that protein targeting is error-prone, and tail-anchored proteins mistargeted to mitochondria are transferred to the endoplasmic reticulum (ER) by an ATPase Msp1 (yeast)/ATAD1 (human) in the mitochondrial outer membrane for further quality examination in the ER to determine their fate, degradation or re-targeting. Analysis of the inter-organelle transfer of proteins requires a combination of time-lapse fluorescence microscopy and a system to achieve regulation of the protein levels of both transfer substrates and factors regulating the transfer in a coordinated manner at precise timing.
View Article and Find Full Text PDFNat Commun
October 2024
Institute of Molecular Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex uses its rhomboid pseudo-protease subunit, Dsc2, to assess the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex likely interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation.
View Article and Find Full Text PDFbioRxiv
August 2024
Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!