Elongin B/C recruitment regulates substrate binding by CIS.
SOCS proteins play a major role in the regulation of cytokine signaling. They are recruited to activated receptors and can suppress signaling by different mechanisms including targeting of the receptor complex for proteasomal degradation. The activity of SOCS proteins is regulated at different levels including transcriptional control and posttranslational modification. We describe here a novel regulatory mechanism for CIS, one of the members of this protein family. A CIS mutant deficient in recruitment of the Elongin B/C complex completely failed to suppress STAT5 activation. This deficiency was not caused by altered turnover of CIS but by loss of cytokine receptor interaction. Intriguingly, no such effect was seen for binding to MyD88. The interaction between CIS and the Elongin B/C complex, which depends on the levels of uncomplexed Elongin B/C, was easily disrupted. This regulatory mechanism may be unique for CIS, as similar mutations in SOCS1, -2, -3, -6, and -7 had no functional impact. Our findings indicate that the SOCS box not only plays a role in the formation of E3 ligase complexes but, at least for CIS, can also regulate the binding modus of SOCS box-containing proteins.
Piessevaux
Julie
J
Department of Medical Protein Research, Flanders Institute for Biotechnology (VIB), Ghent University, A. Baertsoenkaai 3, Ghent, Belgium.
De Ceuninck
Leentje
L
Catteeuw
Dominiek
D
Peelman
Frank
F
Tavernier
Jan
J
D000595:Amino Acid Sequence; D000818:Animals; D000075065:Elongin; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry*
D000075065:Elongin; D053594:Myeloid Differentiation Factor 88; D046988:Proteasome Endopeptidase Complex; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C000616396:ELOB protein, human; C000616401:Elob protein, mouse; C108944:SOCS1 protein, human; C491590:Socs1 protein, mouse