Proteolethargy is a pathogenic mechanism in chronic disease

Alessandra Dall'Agnese; Ming M Zheng; Shannon Moreno; Jesse M Platt; An T Hoang; Deepti Kannan; Giuseppe Dall'Agnese; Kalon J Overholt; Ido Sagi; Nancy M Hannett; Hailey Erb; Olivia Corradin; Arup K Chakraborty; Tong Ihn Lee; Richard A Young

doi:10.1016/j.cell.2024.10.051

Proteolethargy is a pathogenic mechanism in chronic disease

Cell. 2024 Nov 25:S0092-8674(24)01274-1. doi: 10.1016/j.cell.2024.10.051. Online ahead of print.

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
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.