HIPK2 is a highly conserved, constitutively active Ser/Thr protein kinase that is involved in a broad spectrum of biological processes. We have previously reported that the expression of HIPK2 is auto-regulated by a mechanism that depends on the activity of its kinase domain, leading to decreased expression of kinase-dead versus wild-type HIPK2. We have now explored this mechanism in more detail. Differential expression of wild-type and kinase-dead HIPK2 is dependent on sequences located in the C-terminal part of HIPK2, but is only observed when this part of HIPK2 is translated together with the defective kinase domain. On their own, both the defective kinase domain and the C-terminal amino acid sequences are expressed at normal levels and independently of kinase activity. Insertion of a 2A-ribosomal skipping sequence into the HIPK2 coding sequence revealed that the differential expression of wild-type and kinase-dead HIPK2 is caused by degradation of nascent kinase-dead HIPK2. Because HIPK2 is constitutively active and auto-activates its kinase domain already during its translation we speculate that the regulatory mechanism discovered here serves as a quality control mechanism that leads to degradation of nascent kinase molecules with defective kinase domains. Overall our work provides insight into a novel auto-regulatory mechanism of HIPK2 expression, thereby adding a new layer of control to the regulation of HIPK2.

HIPK2是一种高度保守的，组成型活性的Ser / Thr蛋白激酶，与广泛的生物过程有关。我们以前曾报道过，HIPK2的表达是由一种机制自动调节的，该机制取决于其激酶结构域的活性，从而导致激酶死亡与野生型HIPK2的表达降低。现在，我们已经更详细地探讨了这种机制。野生型和激酶死亡的HIPK2的差异表达取决于位于HIPK2的C末端部分的序列，但只有在HIPK2的这一部分与缺陷激酶结构域一起翻译时才能观察到。有缺陷的激酶结构域和C末端氨基酸序列都以正常水平表达，与激酶活性无关。在HIPK2编码序列中插入2A核糖体跳跃序列表明，野生型和激酶死亡的HIPK2的差异表达是由新生的激酶死亡的HIPK2的降解引起的。因为HIPK2具有结构活性，并且在翻译过程中已经自动激活其激酶结构域，所以我们推测这里发现的调节机制是一种质量控制机制，可导致具有缺陷性激酶结构域的新生激酶分子降解。总的来说，我们的工作为HIPK2表达的新型自动调节机制提供了见识，从而为HIPK2的调节增加了新的控制层。因为HIPK2具有结构活性，并且在翻译过程中已经自动激活其激酶结构域，所以我们推测这里发现的调节机制是一种质量控制机制，可导致具有缺陷性激酶结构域的新生激酶分子降解。总的来说，我们的工作为HIPK2表达的新型自动调节机制提供了见识，从而为HIPK2的调节增加了新的控制层。因为HIPK2具有结构活性，并且在翻译过程中已经自动激活其激酶结构域，所以我们推测这里发现的调节机制是一种质量控制机制，可导致具有缺陷性激酶结构域的新生激酶分子降解。总的来说，我们的工作为HIPK2表达的新型自动调节机制提供了见识，从而为HIPK2的调节增加了新的控制层。