Endoplasmic Reticulum: Rough and Smooth

The endoplasmic reticulum (ER) is an interconnected network of membrane tubules and flattened sacs continuous with the nuclear envelope and forming the largest membrane system of the eukaryotic cell. It exists as a ribosome-studded rough form, which synthesises and folds membrane and secretory proteins, and a ribosome-free smooth form, which handles lipid synthesis, detoxification and calcium storage.

Definition

The endoplasmic reticulum is a continuous membrane-bounded network, contiguous with the nuclear envelope, whose rough (ribosome-bearing) regions synthesise and fold proteins entering the secretory pathway and whose smooth regions carry out lipid synthesis, detoxification and calcium storage.

Scope

The entry covers the structural distinction between rough and smooth ER, the co-translational entry of proteins into the rough ER, protein folding and quality control with the unfolded protein response, and the lipid-synthetic, detoxifying and calcium-handling roles of the smooth ER. It is a cell-biology and histology reference topic, not clinical guidance.

Core questions

• How do nascent proteins enter the rough ER and become folded and quality-controlled?
• What distinguishes the rough from the smooth ER structurally and functionally?
• How does the ER sense and respond to accumulation of misfolded protein?
• How does the smooth ER contribute to lipid synthesis and calcium handling?

Key concepts

• Rough versus smooth ER
• Co-translational protein import
• Protein folding and ER quality control
• ER-associated degradation (ERAD)
• Lipid and steroid synthesis
• Calcium storage and the sarcoplasmic reticulum
• Detoxification by smooth ER cytochromes

Key theories

Unfolded protein response (UPR)

Accumulation of unfolded or misfolded protein in the ER lumen is detected by transmembrane sensors that trigger a coordinated transcriptional and translational programme to restore folding capacity or, failing that, to commit the cell to death.

Mechanisms

On the rough ER, ribosomes translating proteins bearing a signal sequence dock at the membrane and thread the nascent chain into or across the bilayer, where it is folded and modified before export. A dedicated quality-control system retains misfolded proteins and targets persistently aberrant ones for retrotranslocation and degradation; when unfolded protein accumulates, transmembrane sensors initiate the unfolded protein response to expand folding capacity or trigger apoptosis. The smooth ER lacks bound ribosomes and is the principal site of phospholipid and steroid synthesis, of drug and toxin metabolism by its oxidising enzymes, and, as the sarcoplasmic reticulum in muscle, of regulated calcium storage and release. The lipid composition generated and maintained here shapes the behaviour of all downstream membranes.

Clinical relevance

ER stress and defects in protein folding and quality control are implicated in a wide range of disease processes, and the smooth ER's drug-metabolising capacity underlies how many xenobiotics are handled by the cell. This entry describes the normal mechanisms that such processes engage and is not a basis for individual diagnostic or treatment decisions.

History

The endoplasmic reticulum was first described by Keith Porter and colleagues in early electron micrographs of cultured cells, and Palade's work tied its rough regions to protein secretion. The signal hypothesis of Blobel and Sabatini explained how proteins are targeted into the rough ER, and later work by Walter, Ron and others defined the unfolded protein response as the organelle's homeostatic stress pathway.

Key figures

• Keith Porter
• George Palade
• Günther Blobel
• Peter Walter
• David Ron

Seminal works

• ron2007
• gardner2013

Frequently asked questions

What is the difference between rough and smooth endoplasmic reticulum?

Rough ER is studded with ribosomes and synthesises and folds proteins for the secretory pathway, whereas smooth ER lacks ribosomes and specialises in lipid synthesis, detoxification and calcium storage.

What is the unfolded protein response?

It is a signalling programme triggered when misfolded proteins build up in the ER; transmembrane sensors act to expand the organelle's folding capacity and, if stress is unresolved, can drive the cell toward death.