생화학분자생물학회

	Cheol-Sang Hwang (hwangcs@korea.ac.kr)
	2023-present	Professor, Department of Life Sciences, Korea University
	2011-2023	Professor, Department of Life Sciences, POSTECH
	2003-2011	Post-doc, Division of Biology, CALTECH
	1996-2003	PhD & Post-doc, Division of Biological Sciences, Seol National University
	1994-1996	MS, Department of Microbiology, Seoul National University
	1990-1994	BSc. Department of Microbiology, Seoul National University

N-terminal formylmethionine as a degron and a specific signal in proteostasis and stress adaptation

N-terminal (Nt) methionine formylation, once thought restricted to bacteria and organelles, is now recognized as a stress-inducible initiator modification in the eukaryotic cytosol. Under metabolic or environmental stress, mitochondrial methionyl-transfer RNA (tRNA) formyltransferase mislocalizes to the cytosol, generating formylated initiator tRNA (fMet-tRNAi) that initiates translation with N-formylmethionine (fMet). Nascent chains bearing Nt-fMet activate an fMet-directed ribosome-associated quality control checkpoint early in elongation, recruiting ribosome-splitting and disaggregation factors. Stalled complexes are routed to stress granules, conserving mRNA, translation machinery, and energy, while limiting aggregation. During prolonged stress, newly synthesized fMet proteins undergo maturation or selective degradation via the fMet/N-degron pathway. In mammals, E3 ligase TRIM52 acts as an Nt-fMet recognin, modulating apoptosis. Proteolytic clearance of cytosolic fMet substrates releases formylated peptides and free fMet, which are elevated in critical illness and activate formyl peptide receptors - linking translation surveillance to innate immune and inflammatory signaling in sepsis and age-related disease. Advances in N-terminomics and anti-fMet reagents now allow direct detection and quantification of cytosolic fMet proteoforms. This Review integrates bacterial and organellar paradigms with emerging cytosolic mechanisms, examines regulatory gating of Nt-formylation, and highlights therapeutic strategies to restore proteostasis and counter fMet-associated pathology.

2026 May;58(5):1370-1382. doi: 10.1038/s12276-026-01723-1
https://pubmed.ncbi.nlm.nih.gov/42104018/