Nuclear role of WASp in gene transcription is uncoupled from its ARP2/3-dependent cytoplasmic role in actin polymerization.

[wiskott-aldrich syndrome]

Defects in Wiskott-Aldrich Syndrome protein (WASp ) underlie development of WAS , an X-linked immunodeficiency and autoimmunity disorder of childhood . Nucleation-promoting factors (NPFs ) of the WASp family generate F-actin in the cytosol via the VCA (verprolin-homology , cofilin-homology , and acidic ) domain and support RNA polymerase II -dependent transcription in the nucleus . Whether nuclear-WASp requires the integration of its actin-related protein (ARP )2 /3 -dependent cytoplasmic function to reprogram gene transcription , however , remains unresolved . Using the model of human TH cell differentiation , we find that WASp has a functional nuclear localizing and nuclear exit sequences , and accordingly , its effects on transcription are controlled mainly at the level of its nuclear entry and exit via the nuclear pore . Human WASp does not use its VCA-dependent , ARP 2 /3 -driven , cytoplasmic effector mechanisms to support histone H 3 K 4 methyltransferase activity in the nucleus of TH 1 -skewed cells . Accordingly , an isolated deficiency of nuclear-WASp is sufficient to impair the transcriptional reprogramming of TBX 21 and IFNG promoters in TH 1 -skewed cells , whereas an isolated deficiency of cytosolic-WASp does not impair this process . In contrast , nuclear presence of WASp in TH 2 -skewed cells is small , and its loss does not impair transcriptional reprogramming of GATA 3 and IL 4 promoters . Our study unveils an ARP 2 /3 :VCA-independent function of nuclear-WASp in TH 1 gene activation that is uncoupled from its cytoplasmic role in actin polymerization .

Diseases
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Diseases presenting "isolated deficiency of cytosolic-wasp" symptom

wiskott-aldrich syndrome

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