Chandrasekaran P, Buckley M, Moore V, Wang LQ, Kehrl JH, Venkatesan S

The human immune deficiency (HIV) Nef protein is an important pathogenic factor that modulates cell surface receptor trafficking and impairs cell motility presumably by interfering at multiple steps with chemotactic receptor signaling. Here, we report that a dominant effect of Nef is to trigger AIP4 E3 ligase mediated Gαi2 ubiquitinylation, ...

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which leads to Gαi2 endolysosomal sequestration and destruction. The loss of the Gαi2 subunit was demonstrable in many cell types in the context of gene transfection, HIV infection or Nef protein transduction. Nef directly interacts with Gαi2 and ternary complexes containing AIP4, Nef and Gαi2 form. A substantial reversal of Gαi2 loss and a partial recovery of impaired chemotaxis occurred following siRNA knockdown of AIP4 or NEDD4, or by inhibiting dynamin. The N-terminal myristoyl group, 62EEEE65 motif, and 72PXXP75 motif of Nef are critical for this effect to occur. Nef expression does not affect a Gqi5 chimera where the five C-terminal residues of Gq are replaced with those of Gαi2. Lysine at position 296 of Gαi2 was identified as the critical determinant of Nef induced degradation. By specifically degrading Gαi2 Nef directly subverts leukocyte migration and homing. Impaired trafficking and homing of HIV Nef expressing lymphocytes likely contributes to early immune dysfunction following HIV infection.

Date: Oct. 15, 2012

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