Abstract
PIWI proteins are key regulators of germline and somatic stem cells throughout different evolutionary lineages. However, how PIWI proteins themselves are regulated remains largely unknown. To identify candidate proteins that interact with PIWI proteins and regulate their stability, here we established a yeast two-hybrid (Y2H) assay in the planarian species Schmidtea mediterranea We show that DNAJA1, a heat shock protein 40 family member, interacts with the PIWI protein SMEDWI-2, as validated by the Y2H screen and co-immunoprecipitation assays. We found that DNAJA1 is enriched in planarian adult stem cells, the nervous system, and intestinal tissues. DNAJA1-knockdown abolished planarian regeneration and homeostasis, compromised stem cell maintenance and PIWI-interacting RNA (piRNA) biogenesis, and deregulated SMEDWI-1/2 target genes. Mechanistically, we observed that DNAJA1 is required for the stability of SMEDWI-1 and SMEDWI-2 proteins. Furthermore, we noted that human DNAJA1 binds to Piwi-like RNA-mediated gene silencing 1 (PIWIL1) and is required for PIWIL1 stability in human gastric cancer cells. In summary, our results reveal not only an evolutionarily conserved functional link between PIWI and DNAJA1 that is essential for PIWI protein stability and piRNA biogenesis, but also an important role of DNAJA1 in the control of proteins involved in stem cell regulation.
Highlights
PIWI proteins are key regulators of germline and somatic stem cells throughout different evolutionary lineages
Our results reveal an evolutionarily conserved functional link between PIWI and DNAJA1 that is essential for PIWI protein stability and PIWI-interacting RNA (piRNA) biogenesis, and an important role of DNAJA1 in the control of proteins involved in stem cell regulation
Two homologs of PIWI-like protein were identified in the planarian Schmidtea mediterranea, and smedwi-2 was found to be essential for planarian regeneration [11]
Summary
Received for publication, June 13, 2018, and in revised form, April 25, 2019 Published, Papers in Press, May 10, 2019, DOI 10.1074/jbc.RA118.004445 Chen Wang‡§, X Zhen-Zhen Yang‡, Fang-Hao Guo§, Shuo Shi‡, Xiao-Shuai Han§, An Zeng§, Haifan Lin‡¶1, and X Qing Jing§2 From the ‡Shanghai Institute of Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China, the §CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the ¶Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06511
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