hTid-1, a Human DnaJ Protein, Modulates the Interferon
Signaling Pathway*
Srijata
Sarkar,
Brian P.
Pollack,
King-Teh
Lin,
Sergei V.
Kotenko,
Jeffry R.
Cook,
Anita
Lewis, and
Sidney
Pestka
From the Department of Molecular Genetics and Microbiology,
University of Medicine and Dentistry of New Jersey, Robert Wood
Johnson Medical School, Piscataway, New Jersey 08854-5635
The Jak family of protein-tyrosine
kinases are crucial for the signaling of a large number of different
polypeptide ligands, including the interferons, many cytokines,
erythropoietin, and growth factors. Through their interaction with
receptors, the Jaks initiate a signaling cascade resulting in the
activation of gene transcription and ultimately a cellular response to
various ligands. In addition to their role in cellular signaling,
alteration of Jak activity has been implicated in several disease
states. In identifying Jak2-interacting proteins with the yeast
two-hybrid system, we cloned the human homologue of the
Drosophila melanogaster tumor suppressor gene lethal
(2) tumorous imaginal discs, which encodes the protein Tid56.
Drosophila Tid56 and its human homologue hTid-1 represent
members of the DnaJ family of molecular chaperones. The
TID1 gene encodes two splice variants hTid-1S
and hTid-1L. We confirmed the interaction between Jak2 and
hTid-1S or hTid-1L by immunoprecipitation from
COS-1 cells expressing these proteins. The interaction between
endogenous hTid-1 and Jak2 was shown in HEp2 cells. We further showed
that hTid-1 interacts with the human interferon-
(Hu-IFN-)
receptor subunit IFN-R2. In addition, using a chimeric construct
where the extracellular domain of IFN-R2 was fused to the kinase
domain of Jak2, we showed that hTid-1 binds more efficiently to the
chimera with an active kinase domain than to a similar construct with
an inactive kinase domain. Additionally, the data demonstrate that
hTid-1 isoforms as well as Jak2 interact with Hsp70/Hsc70 in
vivo, and the interaction between Hsp70/Hsc70 and hTid-1 is
reduced after IFN- treatment. Furthermore, both hTid-1S
and hTid-1L can modulate IFN--mediated transcriptional activity.
*
This work was supported by United States Public Health
Services (USPHS) Grant RO1-CA46465 from the NCI, National Institutes of
Health (NIH) (to S. P.); by USPHS Grants RO1-AI36450, RO1-AI43369, and
2T32AI07403 from the NIAID, NIH (to S. P.); by USPHS Grants RO1-CA46465-12S1 and -13S1 from the NCI, NIH (to S. S.); by State of
New Jersey Commission on Cancer Research Grant 797-007 (to J. R. C.);
by Training Grant 2T32AI007403 from the NIAID, NIH, and a State of New
Jersey Commission on Cancer Research Grant 94-2006-CCR00 (to B. P.);
and by a special award from the Milstein Family Foundation (to S. P.)
for additional support for a variety of efforts in this project.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF411044.
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