My cell biology class didn’t include a thorough introduction to how proteins get degraded, so I did some reading recently to get the very basics.  There are really only two major, fundamentally different mechanisms by which animal cells degrade proteins: the lysosome and the proteasome [introduced in Cooper 2000 Protein Degradation & Lysosome chapters, also reviewed in Mizushima 2008Reinstein & Ciechanover 2006 (ft)].

Both of these are thought to be involved in the degradation of PrP.  A forthcoming post will discuss the evidence for how PrP is degraded.  First, this post will first introduce the basics of these two types of degradation machinery.


The lysosome is a membrane-bound intracellular compartment full of nonspecific proteases that will cleave into individual amino acids any protein they come into contact with.  Proton pumps fill the lysosome with H+ from the cytosol, making it acidic (pH 4.8) — the proteases function optimally at this pH and not at all at cytosolic pH (7.2), thus minimizing the risk to the cell in the event of lysosome rupture.  The lysosome is formed by budding off from a compartment of the late Golgi – it represents an alternate endpoint for some proteins in the secretory pathway that neither stay in the ER or Golgi nor undergo exocytosis to the cell surface.

Proteins destined for lysosomal degradation can reach the lysosome by a variety of means.  Following receptor-mediated endocytosis, endocytic vesicles from the cell surface can fuse with the lysosome; this is a mechanism for degradation of cell surface receptors and thus the downregulation of incoming signals [Cooper 2000 Endocytosis chapter].  In phagocytosis, the cell engulfs foreign bodies – say, invading bacteria, or apoptotic bodies from other cells – and delivers them to the lysosome.  The membrane of the lysosome itself can invaginate, creating exosome-like vesicles full of cytosolic proteins to be degraded.  In “canonical”, starvation-induced autophagy, double membrane forms around material (such as unneeded organelles) in the cytosol and delivers them to the lysosome.  The degradation of proteins in the lysosomes is catabolic – it releases energy – so this response to nutrient starvation recovers some of the energy originally put into synthesizing proteins and other cellular components.  But autophagy isn’t induced only by starvation – unfolded protein stress in the endoplasmic reticulum can cause chunks of ER to be degraded by autophagy [Bernales 2006].

A word about vocabulary: I find that in practice the use of the term “autophagy” is highly promiscuous.  Cooper 2000 defines autophagy narrowly, as “the degradation of cytoplasmic proteins and organelles by their enclosure in vesicles from the endoplasmic reticulum that fuse with lysosomes”.  But others use autophagy interchangeably with lysosomal degradation – for instance, “The major pathways for degradation of cellular constituents are autophagy and cytosolic turnover by the proteasome” [Klionsky & Emr 2000].  The journal Autophagy includes a wide variety of pathways and processes in its purview.  The only lysosomal degradation pathway I haven’t ever seen called autophagy is phagocytosis, perhaps since the engulfment and degradation of foreign bodies doesn’t match the auto in autophagy.


The proteasome is a cylindrical protein complex found in the cytosol which cleaves up proteins tagged with ubiquitin.  To accomplish this, an E1 enzyme activates a ubiquitin molecule, transfers it to an E2 enzyme, and finally an E3 ubiquitin ligase covalently attaches ubiquitin to a lysine (K) on the protein to be degraded.  There are a huge variety of different E3 ubiquitin ligases, reflecting the many different regulatory pathways by which the cell selects and recognizes proteins it wants to flag for degradation.

The proteasome itself weighs in at 26S, and is composed of a 19S gate and a 20S core.  The 19S gate recognizes and binds ubiquitinated proteins, powered by ATP – unlike the lysosome, the proteasome is an energy-losing operation.  Once recognized, these proteins must be de-ubiquitinated and unfold in order to pass through the narrow channel of the 19S and enter the 20S core, a cylindrical complex which does the actual chopping up of proteins.  Unlike the lysosome, where proteases shear proteins up into individual amino acids, the proteasome just chops proteins into small peptides, usually of 7 – 9 amino acids each.  These are later broken into amino acids by cytosolic proteases [Reinstein & Ciechanover 2006 (ft)].

Since it’s located in the cytosol, the proteasome has immediate access to degrade cytosolic proteins.  However, its action is not limited to cytosolic substrates.  Just as proteins can be translocated into the secretory pathway, they can also be retrotranslocated back out in order to be degraded by the proteasome.  This process is called ER-associated degradation or ERAD.  As of today it is not actually known what the channel is that allows for retrotranslocation across the ER membrane.