Impact of ER Protein Homeostasis on Metabolism

  1. Gökhan S. Hotamisligil
  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
  1. Corresponding author: Gökhan S. Hotamisligil, ghotamis{at}hsph.harvard.edu.

Proper regulation of protein homeostasis in a cell is critical for the health of the organism. Proteins, intracellular or secreted, need to be produced and maintained at the right quantity, folded into their three-dimensional conformation with necessary posttranslational modifications, targeted to their correct destinations to insure their optimal function, and degraded efficiently and disposed when needed. The overall process is tightly regulated at many levels to increase or decrease the rate of the synthesis and breakdown of polypeptides. In most cases, failure to properly regulate any one of these control points leads to a dysfunction at the cellular and organismic level resulting in disease.

The endoplasmic reticulum (ER) is a cellular organelle consisting of a vast tubular network, where about one-third of all proteins are synthesized. Proteins secreted to extracellular environment, membrane proteins, and proteins that reside inside the ER lumen are all synthesized and folded into their native conformation in this organelle. Later, most of the posttranslational modifications are completed in the Golgi compartment. Similar to cytoplasmic protein synthesis machinery, ER-mediated protein synthesis involves a complex molecular apparatus to insure the quantity and quality of synthesized proteins (1). ER-mediated protein synthesis and folding represent unique challenges compared with its cytoplasmic counterpart due to the high oxidative environment and high calcium concentrations of the ER lumen (2). Problems arising at the synthesis and folding stages lead to the appearance and accumulation of unfolded proteins in the ER lumen that have to be efficiently cleared using the primary protein degradation machine, the 26S proteasome, which mediates degradation of most of the ER resident as well as cytoplasmic proteins (3). Misfolded proteins, as well as the organelle itself, can also be removed through autophagy (4). Synthesis and degradation machinery interact with each other closely, and it is widely accepted that dysfunction of …

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