The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6

Atsuo Sasaki, Kyoko Inagaki-Ohara, Takafumi Yoshida, Atsushi Yamanaka, Mika Sasaki, Hideo Yasukawa, Antonis E. Koromilas, Akihiko Yoshimura

Research output: Contribution to journalArticle

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Abstract

The suppressor of cytokine signaling-3 (SOCS3/CIS-33/SSI-3) is an important negative regulator of cytokine signaling. Here, we show that an N-terminal truncated isoform (AN-SOCS3) translated from the internal AUG codon 12 was profoundly induced by endoplasmic reticulum (ER) stress- or active double-stranded RNA-activated protein kinase PKR, as a result of induction of eukaryotic initiation factor 2α phosphorylation. ΔN-SOCS3 exhibited a stronger cytokine-inhibitory activity and a higher stability than WT-SOCS3 in Ba/F3 hematopoietic cells. A potential ubiquitination residue, Lys-6, at the N terminus is evolutionary conserved among SOCS3 species. The K6Q-SOCS3 mutant showed a much longer half-life than WT-SOCS3 in Ba/F3 cells. Furthermore, inhibition of the 26 S proteasome pathway increased both ubiquitination and protein levels of WT-SOCS3 but had no effect on K6Q-SOCS3. SOCS3 mutant lacking the carboxyl-terminal SOCS-box exhibited the same stability as K6Q-SOCS3. These observations suggest that the short form of SOCS3 is a naturally occurring stabilized inhibitory protein, whereas WT-SOCS3 is a short-lived protein modulated by Lys-6 ubiquitination and proteasome-dependent degradation. Our findings provide strong evidence for the first time that translational control plays an important role in stabilization and function of SOCS3.

Original languageEnglish
Pages (from-to)2432-2436
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number4
DOIs
Publication statusPublished - 2003 Jan 24
Externally publishedYes

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Initiator Codon
Ubiquitination
eIF-2 Kinase
Protein Isoforms
Proteasome Endopeptidase Complex
Cytokines
Eukaryotic Initiation Factor-2
Phosphorylation
Proteins
Endoplasmic Reticulum Stress
Double-Stranded RNA
Codon
Half-Life
Stabilization
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6. / Sasaki, Atsuo; Inagaki-Ohara, Kyoko; Yoshida, Takafumi; Yamanaka, Atsushi; Sasaki, Mika; Yasukawa, Hideo; Koromilas, Antonis E.; Yoshimura, Akihiko.

In: Journal of Biological Chemistry, Vol. 278, No. 4, 24.01.2003, p. 2432-2436.

Research output: Contribution to journalArticle

Sasaki, Atsuo ; Inagaki-Ohara, Kyoko ; Yoshida, Takafumi ; Yamanaka, Atsushi ; Sasaki, Mika ; Yasukawa, Hideo ; Koromilas, Antonis E. ; Yoshimura, Akihiko. / The N-terminal truncated isoform of SOCS3 translated from an alternative initiation AUG codon under stress conditions is stable due to the lack of a major ubiquitination site, Lys-6. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 4. pp. 2432-2436.
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