Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells’ proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain.

Akt 通常被激活并作为人类癌症的重要靶标。在这项研究中，OTUD1 被确定为 Akt 相关蛋白，并在 Akt 激活时下调。异位 OTUD1 抑制 Akt 磷酸化；然而，它的去泛素化酶活性对这种作用的贡献很小。位于 OTUD1 N 末端固有无序区域的短肽 (OUN-36) 与 Akt PH 结构域强烈结合。PtdIns(3,4,5)P3 识别所需的 PH 域中的残基对于 OUN-36 结合也是必不可少的。OUN-36 优先抑制 Akt 过度活跃的肿瘤细胞增殖并干扰 Akt 细胞膜定位，可能是通过破坏 PH 结构域-PIP3 相互作用。重要的，基于 OUN-36 的疗法有效地消除了响应 MK-2206 治疗的 Akt 反馈再激活，并使癌细胞对化疗和免疫疗法敏感。因此，我们展示了 OTUD1 调节 Akt 活性的机制，并提出了一种通过靶向 Akt PH 结构域实施的潜在的基于肽的癌症治疗策略。