**11. Conclusions**

Although a substantial body of data has been collected on the cellular mechanisms of PAH and FAH protein stability and folding, there remains a major gap in our understanding of how critical components of the PQC system recognize folding defects. The present crystal structure of PAH tetramer increments our understanding of the equilibrium between the alternate native PAH structures (RS-PAH and A-PAH), allosteric binding, and activation by Phe, and the negative regulation and stabilization by BH4 expands our knowledge of the repertoire of disease-associated PAH. There are several excellent reviews describing the structural dynamics and function of the PAH protein. However, our review is the first attempt describing the role of ubiquitination and/or molecular chaperones in PAH protein turnover. Current e fforts to identify successful therapeutic strategies to treat PKU and HT1 still depend on dietary restrictions. Enzyme replacement therapy, gene correction by CRISPR/Cas9, and mRNA therapy are some recently developed breakthrough therapies associated with substantial limitations or problems. PKU and HT1 are complex diseases, with many cellular entities interacting with the substrate proteins (PAH and FAH) and their corresponding mutants, and thus it is laborious to study each of them. However, DUBs and molecular chaperones play a significant role in the triage of misfolded ubiquitinated proteins. Molecular chaperones are already being tested as therapeutic targets, but DUBs are also an attractive target. Even though research supporting the role of DUBs in rescuing the functional mutant proteins is in its infancy, future studies should be directed toward identifying and modulating protein-specific DUBs. As PKU and HT-1 are complex trait diseases, the genotype phenotype correlation plays a significant role in the development of patient-tailored prognostic and therapeutic strategies. Molecular chaperones and DUBs, alone or in combination with other therapies already established for PKU and HT1, have a bright future in treating these proteopathies. E fficient technologies and multidisciplinary methodologies are needed to explore the strong link between molecular chaperones and DUBs and how it can be used to enrich functional mutant proteins and provide new insights into proteopathy medicine.

**Author Contributions:** S.R. and K.-S.K. conceived the idea. N.S. searched the literature and wrote the manuscript. B.S. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript. **Funding:** This work was supported by a gran<sup>t</sup> from the National Research Foundation of Korea (NRF) (2018M3A9H3022412).

**Acknowledgments:** The authors thank all the members of Suri's laboratory for their helpful insights.

**Conflicts of Interest:** The authors declare no conflicts of interest.
