Ter94 ATPase Complex Targets K11-Linked Ubiquitinated Ci to Proteasomes for Partial Degradation

• The Ter94/p97 ATPase drives processing of Hh-regulated transcription factors Ci/Gli
• The Cul1-Slimb (SCFβ-TrCP) E3 ligase adds K11-linked ubiquitin (Ub) chains onto Ci
• Two Ter94 adaptors: Ufd1-like binds Cul1-Slimb and dNpl4 selects K11-linked Ub chains
• Cul1-Slimb specifically adds K11-linked Ub chains to Ci, not to its other substrates

SummaryThe Cubitus interruptus (Ci)/Gli family of transcription factors can be degraded either completely or partially from a full-length form (Ci155/GliFL) to a truncated repressor (Ci75/GliR) by proteasomes to mediate Hedgehog (Hh) signaling. The mechanism by which proteasomes distinguish ubiquitinated Ci/Gli to carry out complete versus partial degradation is not known. Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3R, respectively. Ter94 regulates the partial degradation of ubiquitinated Ci by Cul1-Slimb-based E3 ligase through its adaptors Ufd1-like and dNpl4. We demonstrate that Cul1-Slimb-based E3 ligase, but not Cul3-Rdx-based E3 ligase, modifies Ci by efficient addition of K11-linked ubiquitin chains. Ter94Ufd1-like/dNpl4 complex interacts directly with Cul1-Slimb, and, intriguingly, it prefers K11-linked ubiquitinated Ci. Thus, Ter94 ATPase and K11-linked ubiquitination in Ci contribute to the selectivity by proteasomes for partial degradation.

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