Unveiling Biological Intricacies: Solving the Enigma of Protein Modification

Proteins within human cells frequently experience N-terminal acetylation, a process catalyzed by the enzyme group known as N-terminal acetyltransferases (NATs). Despite the ubiquity of this modification, its function has remained largely enigmatic. Recent advances using CRISPR-Cas9 methodologies and collaborative research involving fruit flies have disclosed that this modification acts as a safeguard against protein degradation, significantly influencing cellular longevity and motility.

Understanding the roles and regulation of proteins is crucial as they are fundamental to all cellular processes.

Professor Thomas Arnesen of the Department of Biomedicine at the University of Bergen stated, “We have long been aware that almost all human proteins undergo specific chemical modifications, but the functional implications of these have not been clearly established.”

Arnesen elucidated, “Among the most prevalent of these modifications is N-terminal acetylation. This involves the addition of an acetyl chemical group at the N-terminus, or starting point, of a protein, mediated by N-terminal acetyltransferases (NATs).” While this modification is pervasive in human cells, its functional significance has remained elusive, according to Arnesen.

Arnesen is a principal investigator in a new study which has identified a fundamental function of N-terminal acetylation—namely, its role in defending proteins against degradation, thereby supporting cellular longevity and motility.

Advances in CRISPR-Cas9 Illuminate the Role of N-terminal Acetylation

To further investigate this issue, molecular biologist Sylvia Varland spent two years at the Donnelly Centre for Cellular & Biomolecular Research at the University of Toronto, Canada. Her work was funded by a FRIPRO mobility grant from the Research Council of Norway. Utilizing cutting-edge CRISPR-Cas9 technology, she conducted comprehensive screening to clarify the functional roles of NAT enzymes in humans. Specifically, Varland focused on NatC, one of the major human NAT enzymes, revealing many human genes that are likely involved in N-terminal acetylation.

“Without the collaborative scientific atmosphere at the Donnelly Center and financial backing from Marie Skłodowska-Curie Actions, this investigation would not have been possible,” Varland remarked.

Upon returning to the Arnesen lab at UiB, Varland examined the molecular ramifications of her genetic findings with the assistance of PhD student Ine Kjosås and other team members. Their biochemical, cellular biology, and proteomics analyses indicated that N-terminal acetylation serves to prevent proteins from being targeted for degradation.

“N-terminal acetylation fundamentally influences a protein’s lifespan and has wide-ranging cellular effects,” Varland noted, adding that similar findings were confirmed in fruit flies, a commonly employed model organism.

N-terminal Acetylation and its Impact on Aging

Simultaneously, investigator Rui Martinho and his research group at the University of Aveiro in Portugal were examining the effects of NatC-mediated N-terminal acetylation using fruit flies. Their collaborative efforts revealed that flies lacking NatC exhibited reduced longevity and motility, which could be partially restored by expressing a specific protein that is conserved between flies and humans and is a key target of NatC.

Deciphering the NatC Conundrum

In sum, through an unbiased global genetic screening coupled with cellular phenotyping, the researchers discovered a general role for N-terminal acetylation in preserving proteins from degradation in human cells. This study illuminates the molecular mechanisms, specifically the ubiquitin ligases, responsible for the degradation of a significant class of human proteins when they lack N-terminal acetylation. The importance of NatC-mediated protein protection is manifest in both human cells and fruit flies, underscoring the critical function of protein N-terminal acetylation in longevity and motility.

“This research demystifies some of the complexities and delineates how N-terminal acetylation dictates the destiny of individual proteins,” concluded Thomas Arnesen.

Acknowledgments

Funding for the Norwegian aspect of this research was sourced from grants provided by the Research Council of Norway, the Health Authorities of Western Norway, the Norwegian Cancer Society, and the European Research Council (ERC).

Reference: “N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity” by Sylvia Varland et al., published on 27 October 2023 in Nature Communications.
DOI: 10.1038/s41467-023-42342-y

Frequently Asked Questions (FAQs) about N-terminal acetylation

More about N-terminal acetylation

• University of Bergen Department of Biomedicine
• Donnelly Centre for Cellular & Biomolecular Research
• Research Council of Norway
• European Research Council (ERC)
• CRISPR-Cas9: A Revolutionary Genetic Engineering Technique
• N-terminal acetylation in Human Cells
• University of Aveiro
• Nature Communications
• Understanding Protein Modification
• Implications of Protein Acetylation