Muhar MF, Farnung J, Cernakova M, Hofmann R, Henneberg LT, Pfleiderer MM, Denoth-Lippuner A, Kalčic F, Nievergelt AS, Peters Al-Bayati M, Sidiropoulos ND, Beier V, Mann M, Jessberger S, Jinek M, Schulman BA, Bode JW, Corn JE. C-terminal amides mark proteins for degradation via SCF-FBXO31. Nature. 2025 Jan 29; Epub 2025 Jan 29 PubMed.
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The Scripps Research Institute, and University of California, San Diego
Redox-mediated damage in the nervous system from both oxidative and nitrosative stress has recently been identified as a prominent contributing factor to many neurodegenerative and neurodevelopmental disorders, and their study may generate novel therapeutic targets (Oh et al., 2024). There are many aberrant redox reactions that can disrupt the function of protein, lipid, DNA, and other cell constituents. Here, Muhar et al. identify a new pathway involving C-terminal amide bearing proteins (CTAPs) that form in response to oxidative stress. What is so intriguing about this pathway is that a CRISPR screen identified FBXO31 as a reader of C-terminal amides that serves as a ubiquitin ligase to tag the CTAPs for degradation, thus getting rid of them. However, the authors report that certain mutations in FBXO31 can cause other substrates (non-amidated) to be degraded and are thus toxic, leading to a neurodevelopmental disorder with intellectual disability. They also raise the possibility that FBXO31-influenced transcriptional responses may be associated with other neurodegenerative diseases.
This is one of several recent studies causally implicating oxidative/nitrosative stress in neurological disease because of the resulting redox reactions, including CTAP, protein S-nitrosylation, alkylation, and sulfonylation. The study of these redox-mediated post-translational modifications (PTMs) is perhaps 50 years behind that of phosphorylation and other better known PTMs, so a lot of work remains to be done.
References:
Oh CK, Nakamura T, Zhang X, Lipton SA. Redox regulation, protein S-nitrosylation, and synapse loss in Alzheimer's and related dementias. Neuron. 2024 Dec 4;112(23):3823-3850. Epub 2024 Nov 7 PubMed.
View all comments by Stuart A. LiptonUniversity of Kansas
From a fundamental biology perspective this is a powerful paper. It emphasizes the importance of post-translational protein modifications, not only in turning certain proteins on or off in terms of function, but also whether certain proteins get to hang around or not. In this case, the post-translational protein modification is c-terminal amide formation, which is induced via oxidative stress.
The authors go on to show a mechanism that removes the marked proteins. We are likely to learn more about such “degron” motifs in the foreseeable future, and I think degron-based models are going to have a role in generating AD model systems because they can be used to selectively eliminate target proteins. As for how these findings ultimately come to inform our understanding of AD, that is, for now, not entirely clear, but as it defines a fundamental area of biology, and stress biology at that, I suspect at some point the AD field will learn from this, even if it is just at a proof-of-concept level.
View all comments by Russell SwerdlowUniversity of Arkansas for Medical Sciences
I found this study very interesting with respect to chemical modification caused by oxidative stress and possibly other metabolic abnormalities. Muhar et al. raise the question of whether C-terminal amidation of proteins plays a role in neurodegeneration. It is possible that C-terminal amidation could shed light on proteinopathies in neurodegenerative diseases such as ALS.
C-terminal amidation is a PTM that involves the addition of an amid group to the C-terminus of a peptide or protein. Currently there is no direct evidence to suggest that C-terminal amidation of proteins causes ALS, however, recently missense mutations in CCNF, encoding for cyclin-F, were found to associate with this disease (Chia et al., 2018). Cyclin-F is a member of the F-Box protein family, which includes FBXO31, and belongs to the FBXO subfamily of F proteins. Muhar et al. describes FBXO31 as a C-terminal reader and a general surveillance factor for C-terminal amides. They provide evidence that CTAPs bind to a conserved pocket in FBXO31, which is interesting given that CTAPs form after oxidative cleavage.
Muhar et al. conducted a fascinating experiment to test how loss of FBXO31 affects transcriptional response and impacts mature neurons, finding that it resembles the RNA-Seq transcriptional signature of familial ALS mutations PFN1(G118V) and TDP-43(G298S) in wild-type and mutant motor neurons.
FBXO31 was discovered as a tumor suppressor factor about 20 years ago. These proteins have a common motif of ~40 amino acids that interacts with SKP1 (S-phase kinase-associated protein 1) and, interestingly, links these to the E3 ubiquitin ligase complex. The protein recycling and degradation machinery in aging neurons is compromised, and abnormally modified proteins aggregate inside and outside of the neurons. Does C-terminal amidation have a role in protein misfolding, oligomerization, fibrilization, and aggregation of mutant or modified proteins?
I agree that there is a potential overlap with ALS-related pathways based on the involvement of oxidative stress and inflammation in ALS disease mechanisms. Muhar et al. open the door to further explore and examine the role of C-terminal amidation and F-Box proteins in the clearance of abnormally modified proteins in neurons that may be subject to the loss of function or gain of toxic function that cause neuronal degeneration in the nervous system.
These findings deserve to be recognized as a new frontier area of neuronal biology that should be investigated to better understand the mechanism of neurodegeneration. They describe the C-terminal amides as “degrons” that may provide an opportunity to develop therapeutic strategies to block neurodegeneration.
References:
Chia R, Chiò A, Traynor BJ. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol. 2018 Jan;17(1):94-102. Epub 2017 Nov 16 PubMed.
View all comments by Mahmoud KiaeiMake a Comment
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