Human MxB Protein, an Interferon-α-inducible GTPase, Contains a Nuclear Targeting Signal and Is Localized in the Heterochromatin Region beneath the Nuclear Envelope

Abstract

Interferon-inducible Mx proteins belong to the family of large GTPases and are highly homologous with dynamins within their GTP-binding domain. Cytoplasmically localized human MxA protein mediates resistance to influenza and several other viruses, whereas human MxB protein has not been found to have any antiviral activity. Here we show that MxB protein is found both in the cytoplasm and in the nucleus, where it is localized in a granular pattern in the heterochromatin region beneath the nuclear envelope. Transfection experiments in COS cells of N-terminally deleted MxB constructs revealed a functional nuclear localization signal within the first 24 N-terminal amino acids. Nuclear 78-kDa and cytoplasmic 76-kDa forms of MxB protein were found in all of the cell lines studied and in human peripheral blood mononuclear cells. MxB protein proved to be a functional GTPase with activity comparable to that of MxA protein. N-terminally truncated (delta1-82) MxB protein lacking both the nuclear localization signal and a proline-rich domain had almost completely lost its GTPase activity. Analysis of peripheral blood mononuclear cells suggested that MxB protein expression is strictly regulated by interferon-alpha. This is the first documentation that human Mx protein resides in the nucleus. It also emphasizes that there are considerable differences in the localization and structure of functional domains within Mx proteins.

Differentially Expressed Genes in Two LNCaP Prostate Cancer Cell Lines Reflecting Changes during Prostate Cancer Progression

“…Cytoplasmic human MxA protein mediates resistance to multiple RNA viruses, whereas no antiviral activity has been found for human MxB protein (Melen et al, 1996). The genes for MxA and MxB are located in the same chromosomal area as the TM-PRSS2 gene, 21q22.3 (Paoloni-Giacobino et al, 1997).…”

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

“…The myxovirus B (MxB) gene was originally cloned from a human glioblastoma cell line treated with alpha interferon (IFN-␣) (4,5). MxB as well as the related protein MxA belong to the dynamin-like family of proteins, which have diverse functions ranging from vesicle transport to antiviral activity (1,(6)(7)(8)(9)(10)(11).…”

“…MxB contains a previously described putative nuclear localization signal on its N-terminal 25 amino acids (4). Deletion of the N-terminal 25 amino acids annihilates the ability of MxB to block HIV-1 infection and to bind to the HIV-1 core (23,24,27).…”

La protéine MX2 humaine est l’un des acteurs de la réponse interféron contre le VIH-1

“…En effet, alors que l'ADN viral s'accumule normalement en présence de MX2, aucune de ses formes nucléaires n'est retrouvée (que ce soit l'ADN viral intégré dans le génome cellulaire, ou bien les cercles à deux long terminal repeat, ou LTR, qui sont des formes épisomales de l'ADN viral ne pouvant être formées que dans le noyau). De façon intéressante, la protéine MX2 semble être localisée au niveau de l'enveloppe nucléaire [8,9], ce qui est en adéquation avec un blocage potentiel au niveau de l'import nucléaire de l'ADN viral. Afin d'évaluer directement le rôle de MX2 dans la réponse cellulaire contre le VIH-1 induite par l'IFN, son expression a été inhibée à l'aide de la technique d'interférence par ARN.…”

“…In vivo, la délétion de cIAP1 diminue la croissance des tumeurs xénogreffées chez la souris nude et retarde fortement le dévelop-pement de nodules cancéreux pulmonaires après injection de cellules tumorales dans la veine caudale [9]. Un traitement de cellules tumorales par un antagoniste des IAP conduit aussi à des changements morphologiques importants avec un allongement des cellules et l'apparition de protubérances à leur surface [8,10] [1][2][3]. Cependant, le virus a souvent appris à éviter les produits de ces gènes, nommés facteurs de restriction, soit en utilisant des protéines virales antagonistes, soit en mutant l'élément viral ciblé [3].…”