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UniProt release 2016_07

Published July 6, 2016


(Bacterial) immigration under control

Essentially all our mucosal surfaces are covered by microorganisms, not only bacteria, but also archaea, fungi, protozoans and viruses. Most of them reside within the gastrointestinal tract. Normal gut flora is largely responsible for overall health of the host and it does not trigger any inflammatory response… as long as it remains where it belongs. In order to maintain a subtle, though strict segregation, the colonic epithelium is covered by mucus. The latter is organized in 2 layers. The inner layer adheres firmly to the epithelial cells. It is dense and does not allow bacterial penetration, thus keeping the epithelial cell surface free from bacteria. The outer layer is the habitat of the commensal flora. The inner mucus layer is converted into the outer layer by proteolytic activities provided by the host and also probably by commensal bacterial proteases and glycosidases.

Colonic quietness is not only maintained by the mucus physical barrier, the immune system plays also a crucial role, among others, through the secretion of IgA into the gut lumen. These dimeric immunoglobulins bind flagellin, a highly conserved protein component of the bacterial flagellum that is expressed by many different commensal species. This interaction limits the association of flagellated bacteria with the intestinal mucosa. The mechanism leading to IgA production by B cells in this context is not yet fully uncovered, but it is known that flagellin is sensed by at least 3 different innate immune receptors, including TLR5, which plays an instrumental role in this process.

In this peaceful, though cautious cohabitation, another host protein actor has been recently identified, LYPD8. In the absence of LYPD8, bacteria penetrate the inner mucus layer despite normal mucin production, the main building block of mucus, and further into the crypts of the large intestine, causing severe inflammation. LYPD8 is membrane protein, attached to the plasma membrane through a glycophosphatidylinositol (GPI) anchor. It is selectively expressed in epithelial cells at the uppermost layer of the large intestinal gland and can be released into the gut lumen by the action of specific phospholipases. Once in the extracellular milieu, it binds to flagellated bacteria, including Proteus mirabilis. Contrary to TLR5, this interaction seems to be specific to flagella, a higher order structure comprised of polymerized flagellins, not to monomeric flagellins. This binding severely impairs bacterial swarming activity, thereby regulating gut homeostasis.

Until these recent observations, nothing was known about LYPD8. It had only been identified through large scale cDNA and genome sequencing. The sole annotations provided in UniProtKB were based on protein domain predictions, including that of the GPI anchor (UPAR/Ly6 domain) and of the signal peptide. As of this release, LYPD8 entries have been updated with this new functional information and are publicly available.

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Deleted diseases

  • Ciliary dyskinesia, primary, 31
  • Jensen syndrome
  • Mental retardation, autosomal dominant 12
  • Thiopurine S-methyltransferase deficiency