Reactome | Nef Mediated CD4 Down-regulation

Nef Mediated CD4 Down-regulation

Stable Identifier

R-HSA-167590

Type

Pathway

Species

Homo sapiens

Related Species

Human immunodeficiency virus 1

ReviewStatus

5/5

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Disease (Homo sapiens)

- Infectious disease (Homo sapiens)
  - Viral Infection Pathways (Homo sapiens)
    - HIV Infection (Homo sapiens)
      - Host Interactions of HIV factors (Homo sapiens)
        
        The role of Nef in HIV-1 replication and disease pathogenesis (Homo sapiens)
        
        Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters (Homo sapiens)
        
        Nef Mediated CD4 Down-regulation (Homo sapiens)

General

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The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD4. CD4 has its own internalization motif, though this motif is normally concealed by CD4 interaction with Lck, a tyrosine kinase. Nef is known to disrupt this interaction and then facilitate a cascade of protein interactions that ultimately result in the degradation of internalized CD4 protein. The final set of protein interactions that direct Nef to the beta-subunit of the COPI coatomers are at this time unclear.

A benefit for the virus from CD4 down-modulation is abolition of interaction between the receptor and the Env protein of the budding virus, which likely increases HIV release from infected cell as well as infectivity of viral particles.

Literature References

PubMed ID	Title	Journal	Year
2014052	Serine phosphorylation-independent downregulation of cell-surface CD4 by nef Miller, AD, Garcia, JV	Nature	1991
11264384	Direct in vitro binding of full-length human immunodeficiency virus type 1 Nef protein to CD4 cytoplasmic domain Baur, AS, Willbold, D, Preusser, A, Briese, L	J Virol	2001
7831289	Human immunodeficiency virus type 1 Nef and p56lck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail Salghetti, S, Mariani, R, Skowronski, J	Proc Natl Acad Sci U S A	1995
8124721	Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain Konner, J, Trono, D, Lenburg, ME, Landau, NR, Aiken, C	Cell	1994
8756680	The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR. Stahl, SJ, Wingfield, PT, Grzesiek, S, Bax, A	Biochemistry	1996

Participants

Events

Participates

as an event of

Nef-mediates down modulation of cell surface receptors by recruiting them to clathrin adapters (Homo sapiens)

Event Information

Go Biological Process

mitigation of host antiviral defense response (0019049)

Disease

Name	Identifier	Synonyms
Human immunodeficiency virus infectious disease	DOID:526	HIV infection

Authored

Gillespie, ME (2007-07-25)

Reviewed

Skowronski, J (2007-08-07)

Created

Gillespie, ME (2005-10-20)