Proteolethargy is a pathogenic mechanism in chronic disease

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: tlee@wi.mit.edu.
⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.

PMID: 39610243
PMCID: PMC11724756 (available on 2026-01-09)
DOI: 10.1016/j.cell.2024.10.051

Proteolethargy is a pathogenic mechanism in chronic disease

Alessandra Dall'Agnese et al. Cell. 2025.

. 2025 Jan 9;188(1):207-221.e30.

doi: 10.1016/j.cell.2024.10.051. Epub 2024 Nov 27.

Authors

Affiliations

¹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
⁸ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: tlee@wi.mit.edu.
⁹ Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: young@wi.mit.edu.

PMID: 39610243
PMCID: PMC11724756 (available on 2026-01-09)
DOI: 10.1016/j.cell.2024.10.051

Abstract

The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here, we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia, and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases.

Keywords: chronic disease; cysteine; protein mobility; proteolethargy; reactive oxygen species; signaling.

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Conflict of interest statement

Declaration of interests The Whitehead Institute has filed a patent application based on this paper. A.D. is a consultant for Dewpoint Therapeutics. A.K.C. is a consultant (titled “Academic Partner”) of Flagship Pioneering, a consultant and member of the Strategic Oversight Board of Apriori Bio (a Flagship company), and a consultant and SAB member of Metaphore Bio (a Flagship company). R.A.Y. is a founder or shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, Dewpoint Therapeutics, Paratus Sciences, and Precede Biosciences and has an advisory role at Novo Nordisk.

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Proteolethargy is a pathogenic mechanism in chronic disease

Affiliations

Proteolethargy is a pathogenic mechanism in chronic disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous