Interferon binding and signaling

[gocentral]

Hello,

Can we align the nomenclature for interferon receptors and signaling terms ?

For example we have

• type I interferon receptor activity (MF)
• type I interferon-mediated signaling pathway (BP)

but interferon-alpha/beta receptor binding (MF) (which is a type of interferon I). (or the latter term needs a parent Type I interferon receptor binding?)

Same comment applies for all interferon types.

It seems like the Type I, II, III distinction is the most useful: http://en.wikipedia.org/wiki/Interferon

Thanks,

Pascale

Reported by: pgaudet

Original Ticket: geneontology/ontology-requests/10531

[gocentral]

• assigned_to: RFoulger

Original comment by: ukemi

[gocentral]

We should go ahead and axiomatize these using PRO and outsource this issue (although this will take a bit of work on our part - e.g. PRO lacks the "interferon" grouping class).

The receptor hierarchy may not be completely parallel if the receptors are complexes.

We have:

 / GO:0003674 ! molecular_function
  is_a GO:0005488 ! binding
   is_a GO:0005515 ! protein binding
    is_a GO:0005102 ! receptor binding
     is_a GO:0005126 ! cytokine receptor binding
      is_a GO:0005132 ! interferon-alpha/beta receptor binding

The receptor has as parts IFNAR1 and IFNAR2. Do we mean that GO:0005132 binds to either of the two members (in which case this should be clear) or binds to the complex (in which case this should be under complex binding).

Should we also not have the complex in GO CC?

Original comment by: cmungall

[gocentral]

• labels: --> signaling

Original comment by: rebeccafoulger

[gocentral]

Hi Pascale and Chris,

Both type I/II/III and the alpha/beta/gamma/delta etc groupings are valid. PRO has:

type I interferon ; PR:000025848 --[isa]interferon alpha ; PR:000024938
--[isa]interferon beta ; PR:000024939
--[isa]interferon delta ; PR:000030047
--[isa]interferon epsilon ; PR:00008925
--[isa]interferon kappa ; PR:000008927
--[isa]interferon omega ; PR:000025020
--[isa]interferon tau ; PR:000025021

type II interferon ; PR:000024990
--[isa]interferon gamma ; PR:000000017

interferon lambda ; PR:000001362 (exact synonym: interferon type III)

The type I split is as we have in GO. The type II/gamma and type III/lambda is slightly different: in GO we have type II interferon and gamma interferon as synonymous. And have type III interferon as the grouping class.

I'd want PRO to check their hierarchy before I change all our GO terms (our GO terms match Reactome). What's the process for requesting changes/checks in PRO now?

In the meantime I've done the following edits:

1. new terms: type III interferon signaling pathway ; GO:0038196 type I interferon receptor complex ; GO:0038197

2. Created missing P/F links

3. Based on PMID:17502368 (among others), renamed interferon-alpha/beta receptor binding ; GO:0005132

   type I interferon receptor binding ; GO:0005132

Like Chris says: the type I receptor is a heterodimeric receptor. Sometimes called the alpha/beta receptor but I've renamed it because it can bind to type I interferons other than interferon alpha and beta. PRO have: interferon-alpha/beta receptor alpha chain ; PR:000008922 interferon-alpha/beta receptor beta chain ; PR:000008923 We mean that the protein can bind to either (or both) of the subunits; some papers say just one subunit is involved in ligand binding.

The 'protein complex binding' discussion has come up before. In most cases, I assume we mean binding to one protein in a complex. In some cases I assume we mean binding to all subunits of a complex (e.g. for a receptor complex where both subunits are required to form a ligand-binding site). AFAIK, we don't distinguish between these cases at the moment.

Becky

Original comment by: rebeccafoulger

[gocentral]

Thanks Becky !

Original comment by: pgaudet

[gocentral]

Feedback from Darren Natale, on the classification of interferons in PRO:

We did quite a bit of looking at how interferons were classed when we made the terms in PRO. Here are some references, followed by our reasoning.

http://www.ncbi.nlm.nih.gov/pubmed/15939626 "Type II IFN is identical to IFN-gamma"

(implies synonymy, supporting the GO view)

http://www.ncbi.nlm.nih.gov/pubmed/15546383 "the single Type II IFN, IFN-γ"

(implies subclass, supporting the PRO view)

I initially found this next one a bit confusing. It implies that the alpha/beta/gamma system is a classification of the interferons, while the type I/II/III system is a classification of the interferon receptors. Later I determined that the I/II/III system became a classification of interferons based on receptor types.

http://www.ncbi.nlm.nih.gov/pubmed/2525482 "The alpha-IFNs and beta-IFN bind to a common receptor (type I),

whereas gamma-IFN binds to a separate receptor (type II)."

The origins of the type I/II nomenclature: http://www.jimmunol.org/content/111/6/1914.long

The origins of the alpha/beta/gamma nomenclature: http://cancerres.aacrjournals.org/content/40/10/3860.full.pdf

http://link.springer.com/article/10.1007%2FBF01309277#page-1

I think this summarizes the issue:

http://www.aepress.sk/acta/full/av697j.pdf "IFNs were initially classified based on cell types from which they were derived, their chemical properties and their antigenicity (Stewart, 1979). Three types of IFNs were recognized: leukocyte (alpha), fibroblast (beta) and immune (gamma)...With the cloning of IFN molecules this nomenclature has also evolved, recently being based primarily on the structure of IFN genes and proteins. In mammals, there are six IFN families designated alpha, beta, gamma, delta, omega and tau. These IFNs have been grouped into two separate classes: type I and II. The type I IFN comprises IFN families alpha, beta, omega, tau and delta, the type II IFN

contains IFN-gamma only."

In fact, the type I/II nomenclature pre-dates the alpha/beta/gamma designation. The type I/II classification was initially based on biophysical properties of the proteins, while the alpha/beta/gamma classification was based on cell types. The latter was later extended to new types based on sequence/evolutionary considerations. As it turned out, alpha and beta (and most of the new types) were found to be evolutionarily related, and thus all were considered type I. However, nomenclature criteria do indeed evolve, and so far as I can tell, the alpha/beta/gamma criterion has become principally based on evolution of the genes/proteins, while the type I/II (and, later, III) has become receptor type (so, not only are all type I interferons more closely related by sequence, they use the same type of receptor).

Considering all this, we decided both classification schemes are valid and distinguishable, and that the 'gamma is a synonym for type II' viewpoint is somewhat misleading (even though gamma is the only member of the type II thus found) because the classification criteria differ. Calling them synonyms would thus be like saying "all people who sit in office 1220 in the PIR suite at Georgetown University" and "all people with the designation 'Darren A. Natale, PhD'" are synonyms, simply because they both (currently) include only me.

This brings me to IFNlambda. Our initial reading indicated that the type III and lambda designations seemed to arise simultaneously and seemed to use the same criteria to distinguish them from the other interferons. I have since modified my stance, having discovered more information. I believe the lambda designation is due to the sequence divergence: "The members of the IFN- family occupy a space between the previously defined IL-10 family and the type I IFNs in terms of their evolutionary emergence." (http://www.nature.com/ni/journal/v4/n1/full/ni875.html); the type III designation comes from the distinct receptor type used: "They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through a heterodimeric receptor complex that is different from the receptors used by type I or type II IFNs." (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925029/). We should therefore make lambda a child of type III rather than a synonym, similar to the relationship between gamma and type II.

Original comment by: rebeccafoulger

[gocentral]

• status: open --> closed-fixed

Original comment by: rebeccafoulger

[gocentral]

Based on the feedback from Darren Natale, we will take the following classification of interferons:

type III interferon --[isa]interferon lambda

type II interferon ; PR:000024990 --[isa]interferon gamma ; PR:000000017

I haven't created new terms in GO, but have adjusted the synonym types to BROAD/NARROW accordingly. And updated the definitions to add in comments:

Interferon gamma is the only member of the type II interferon found so far. Interferon lambda is the only member of the type III interferon found so far.

So this should be more consistent at least. If other type II/III interferons are found, new terms can be added accordingly.

Thanks, Becky

Original comment by: rebeccafoulger