TRIM22 orchestrates the proliferation of GBMs and the benefits of TMZ by coordinating the modification and degradation of RIG-I

Abstract

Tripartite motif 22 (TRIM22) is an agonist of nuclear factor κB (NF-κB) that plays an important role in the proliferation and drug sensitivity of glioblastoma (GBM). However, the molecular mechanism underlying the protein network between TRIM22 and nuclear factor κB (NF-κB) in GBM remains unclear. Here, we found that knockout of TRIM22 effectively inhibited tumor proliferation and increased the sensitivity of GBM cells to temozolomide (TMZ) in vivo and in vitro. Moreover, TRIM22 forms a complex with cytosolic purine 5-nucleotidase (NT5C2) in GBM and regulates the ubiquitination of retinoic acid-inducible gene-I (RIG-I). TRIM22 promotes the K63-linked ubiquitination of RIG-I, while NT5C2 is responsible for K48-linked ubiquitination. This regulation directly affects the RIG-I/NF-κB/cell division cycle and apoptosis regulator protein 1 (CCAR1) signaling axis. Ubiquitin modification inhibitor of RIG-I restores the inhibition of tumor growth induced by TRIM22 knockout. The follow-up results showed that compared with patients with high TRIM22 expression, patients with low TRIM22 expression had a longer survival time and were more sensitive to treatment with TMZ. Our results revealed that the TRIM22-NT5C2 complex orchestrates the proliferation of GBM and benefits of TMZ through post-translational modification of RIG-I and the regulation of the RIG-I/NF-κB/CCAR1 pathway and is a promising target for single-pathway multi-target therapy. Tripartite motif 22 (TRIM22) is an agonist of nuclear factor κB (NF-κB) that plays an important role in the proliferation and drug sensitivity of glioblastoma (GBM). However, the molecular mechanism underlying the protein network between TRIM22 and nuclear factor κB (NF-κB) in GBM remains unclear. Here, we found that knockout of TRIM22 effectively inhibited tumor proliferation and increased the sensitivity of GBM cells to temozolomide (TMZ) in vivo and in vitro. Moreover, TRIM22 forms a complex with cytosolic purine 5-nucleotidase (NT5C2) in GBM and regulates the ubiquitination of retinoic acid-inducible gene-I (RIG-I). TRIM22 promotes the K63-linked ubiquitination of RIG-I, while NT5C2 is responsible for K48-linked ubiquitination. This regulation directly affects the RIG-I/NF-κB/cell division cycle and apoptosis regulator protein 1 (CCAR1) signaling axis. Ubiquitin modification inhibitor of RIG-I restores the inhibition of tumor growth induced by TRIM22 knockout. The follow-up results showed that compared with patients with high TRIM22 expression, patients with low TRIM22 expression had a longer survival time and were more sensitive to treatment with TMZ. Our results revealed that the TRIM22-NT5C2 complex orchestrates the proliferation of GBM and benefits of TMZ through post-translational modification of RIG-I and the regulation of the RIG-I/NF-κB/CCAR1 pathway and is a promising target for single-pathway multi-target therapy. IntroductionGlioma is the most common malignancy of the central nervous system, and patients with high-grade gliomas have a poor prognosis and short survival.1Laws E.R. Parney I.F. Huang W. Anderson F. Morris A.M. Asher A. Lillehei K.O. Bernstein M. Brem H. Sloan A. et al.Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project.J. Neurosurg. 2003; 99: 467-473Crossref PubMed Scopus (547) Google Scholar The use of temozolomide (TMZ) can significantly prolong the survival of patients with high-grade glioma, but drug resistance is increasingly becoming prevalent in patients with this disease.2Lee E.S. Ko K.K. Joe Y.A. Kang S.G. Hong Y.K. Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells.Oncol. Lett. 2011; 2: 115-121Crossref PubMed Scopus (29) Google Scholar,3Xiao-Xing L.I. Wang Z.M. Zuo J.L. Qi-Nian X.U. Wang X.Y. Tao C. Establishment of drug-resistance cell line of human glioma induced by temozolomide and reversion of drug-resistance.Suzhou Univ. J. Med. Sci. 2007; 27: 169-171Google Scholar As cancer treatment has entered the era of targeted molecular therapy,4Yamanaka R. Molecular-targeted therapy for malignant glioma.Brain Nerve. 2009; 61: 177-188PubMed Google Scholar many glioma-associated gene mutations, such as the 19q deletion, have been discovered in recent years.5von Deimling A. Louis D.N. von Ammon K. Petersen I. Wiestler O.D. Seizinger B.R. Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.Cancer Res. 1992; 52: 4277-4279PubMed Google Scholar The targeted therapies currently used for glioma include the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib,6Chang C.Y. Kuan Y.H. Ou Y.C. Li J.R. Wu C.C. Pan P.H. Chen W.Y. Huang H.Y. Chen C.J. Autophagy contributes to gefitinib-induced glioma cell growth inhibition.Exp. Cell Res. 2014; 327: 102-112Crossref PubMed Scopus (35) Google Scholar the vascular endothelial growth factor receptor inhibitor avastin,7Koukourakis G.V. Has bevacizumab (avastin) given extra therapeutic gain in metastatic colorectal cancer and malignant brain gliomas? Systematic review answering this question.Recent Pat. Inflamm. Allergy Drug Discov. 2012; 6: 70-77Crossref PubMed Scopus (8) Google Scholar and the anti-CD20 monoclonal antibody rituximab.8Irani S.R. Gelfand J.M. Bettcher B.M. Singhal N.S. Geschwind M.D. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy.JAMA Neurol. 2014; 71: 896-900Crossref PubMed Scopus (82) Google Scholar It is hoped that therapies targeting multiple signaling pathways or multiple targets in the same signaling pathway are more effective than therapies with single targets. Clinical trials for glioma investigational drugs, such as marimastat in combination with M.D. of temozolomide the in and glioblastoma PubMed Scopus Google Scholar and in combination with and in glioblastoma patients Google Scholar have motif 22 a of the is in a of such as cell F. Chen W. J. Wang H. TRIM22 promotes and of glioblastoma by C.J. a and 2012; PubMed Google Scholar C.J. a and 2012; PubMed Google K. of the gene TRIM22 is of human Res. 2007; PubMed Scopus Google Scholar M. M.D. in human cells to and of high and PubMed Scopus Google Scholar and C. Chen apoptosis is associated with in PubMed Scopus Google Scholar to and W. of TRIM22 as a Res. PubMed Scopus Google Scholar is used as a for targeted therapy in the of many TRIM22 the of cancer through the factor κB (NF-κB) signaling pathway and M. W. K. TRIM22 cancer through the signaling pathway and a J. Google Scholar However, to has revealed the role of TRIM22 in glioma, that TRIM22 signaling in glioblastoma by the of J. K. Chen A. Li F. Huang Li Wang J. TRIM22 signaling in glioblastoma by the of PubMed Scopus Google Scholar The of targeting has from in Chen Wang Li Inhibition of results in and by gene Lett. PubMed Scopus Google Scholar However, with the of by this inhibitor and the of treatment with this inhibitor on multiple is to a targeted drug that can used in combination with However, the pathway plays an role in many is by and can gene has been found that TRIM22 can the the mechanism between TRIM22 and is are the role of TRIM22 in GBM and the protein network mechanism between TRIM22 and for targeted combination therapies for is in gliomas and is with tumor and the expression of TRIM22 in we the and and found that TRIM22 in GBM compared with brain TRIM22 has been as a target gene of J. M. C. K. The target gene TRIM22 directly or with the factor and the of to 2012; PubMed Scopus Google Scholar and the showed that is the gene with the in gliomas we that high TRIM22 expression plays an role in to the results we from the The results showed that TRIM22 in gliomas compared with brain and with tumor we on cell and GBM found that TRIM22 more in cells than in and cells and that TRIM22 more in gliomas than in gliomas of the role of TRIM22 in we cells The 1 used as the while the we found that the a of and that the significantly between the and and the in the had survival than in the but in between the results that TRIM22 GBM cell proliferation in we the survival of patients with glioma with TRIM22 expression the found that the survival and survival of patients with GBM were to the expression of However, patients with glioma with low TRIM22 expression had results were with the results of et J. K. Chen A. Li F. Huang Li Wang J. TRIM22 signaling in glioblastoma by the of PubMed Scopus Google Scholar that TRIM22 is with a poor survival in with we that the results to the of patients in the and that TRIM22 with poor survival in and are to the between TRIM22 expression and high-grade knockout significantly inhibited the proliferation of gliomas in vivo and in and the benefits of the of TRIM22 knockout on glioma and on TMZ we cell and and short and to the of we TRIM22 in the and cell found that TMZ treatment and knockout of TRIM22 significantly inhibited glioma cell as by the and inhibited the cell cycle to the of TRIM22 the sensitivity of GBM cells to TMZ. cells with the most in for of showed that the expression of and increased TMZ treatment and TRIM22 knockout. the expression of and Wang J. Chen C. Chen W. Wang C. R. glioma and by cell cycle and the Res. PubMed Scopus Google Scholar showed the results that TMZ and TRIM22 can the glioma cell cycle to the and that TRIM22 knockout can the of TMZ on the cell the Cell results showed that TMZ and TRIM22 knockout significantly cell we found that the proliferation of the TRIM22 knockout cell than that of the tumor of TRIM22 with TMZ tumor inhibition and survival and and we and glioma from the of and found that patients with high TRIM22 expression had a in and protein of TRIM22 proliferation of GBM in vivo and in The of TMZ treatment and knockout of TRIM22 on and cell by and used to cell cycle in and of protein expression in Cell vivo in of treatment on the tumor The survival of in used to TRIM22 and expression in Clinical were for TRIM22 and expression by is used as a protein to the in and showed that TMZ treatment apoptosis in apoptosis in and cells TMZ treatment and we found that TRIM22 knockout and TMZ treatment had on glioma cell and and as by the results of the and induced by TMZ treatment or TRIM22 expression in of the cell used in this data that the knockout of TRIM22 glioma proliferation and glioma cell resistance to to NT5C2 and the RIG-I TRIM22 promotes glioma proliferation and on TMZ we the of TRIM22 in cells and The results of showed that the most to to TRIM22 were cytosolic purine 5-nucleotidase cell division cycle and apoptosis regulator protein 1 1 and protein The were to a protein network the between and we used a for The of the expression of protein in of gliomas on the and of patients in the with high NT5C2 and expression had or However, in gene between the and GBM in the data from the that and were in pathways to tumor proliferation and the cell cycle The results of the that a between the of the to results that TRIM22 the of TRIM22 and results of between of of of protein and of in results in GBM and of by NT5C2 expression in of by NT5C2 expression in of by expression in expression of and in GBM and in the The of for between TMZ and TMZ on cells and of results showed that the between the TMZ and the knockout TMZ were in and the RIG-I signaling and are the in we are in this we the RIG-I signaling pathway for and and data that TRIM22 with NT5C2 and that the mechanism the RIG-I signaling of TRIM22 the proliferation of GBM cells by the expression of to the RIG-I/NF-κB/CCAR1 is a of the RIG-I of RIG-I in and signaling of RIG-I in PubMed Scopus Google Wang P.H. M. J.R. and are associated with of and of signaling pathway in Res. PubMed Scopus Google M. et protein to by with the and signaling 2011; PubMed Scopus Google Scholar and et J. K. Chen A. Li F. Huang Li Wang J. 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PubMed Scopus Google Scholar we found that and have a with in the from to to the and a of we a in and found that and the of the expression significantly with factor and that and the expression of and that this with TRIM22 treatment with for an of RIG-I, the in and while low TRIM22 expression inhibited expression we that is the in the RIG-I pathway that regulates the cell cycle and in vivo were tumor the to the we in and found that the expression of RIG-I, and were in the than in the and the we used a to and found that with the expression of RIG-I, or significantly the glioma cell the of the of glioma cells results that TRIM22 the proliferation of GBM cells by the expression of to the RIG-I/NF-κB/CCAR1 to NT5C2 as a to the RIG-I TRIM22 regulates the RIG-I pathway and the we in cells to the between TRIM22 and RIG-I, or The results showed that TRIM22 with NT5C2 and RIG-I but to or RIG-I in the results but in the results showed that cells with and that showed that TRIM22 and NT5C2 were results of protein and ubiquitination of results for TRIM22 to RIG-I, and antibody for TRIM22 and with a of for of and used to the expression of NT5C2 and RIG-I of with and to the combination of and RIG-I in of RIG-I in in vivo cells were with for by and is used as a protein to the in the cells were with protein and found that TRIM22 and NT5C2 protein expression significantly and while RIG-I showed a This by the of and found that TRIM22 and had on the of but TRIM22 significantly RIG-I we that TRIM22 and NT5C2 RIG-I ubiquitination. the the we and cells and the between the TRIM22 and the a antibody and an protein found that TRIM22 to NT5C2 and RIG-I and we with and found that RIG-I on and but on or TRIM22 the expression of NT5C2 in the that NT5C2 and RIG-I the of the K48-linked ubiquitination of RIG-I with that of the K63-linked ubiquitination of RIG-I with that of TRIM22 data that NT5C2 is responsible for the K48-linked ubiquitination of RIG-I and that TRIM22 is responsible for the K63-linked ubiquitination of we used and for The results that RIG-I and found that RIG-I on TRIM22 a low RIG-I in the of low NT5C2 expression results an between TRIM22 and TRIM22 regulates the K63-linked ubiquitination of RIG-I, NT5C2 regulates the K48-linked ubiquitination of and NT5C2 the RIG-I/NF-κB/CCAR1 as an regulates protein ubiquitination. the RIG-I expression is TRIM22 is with the the role of TRIM22 in this pathway we a and found that of TRIM22 or NT5C2 significantly the expression of and the of TRIM22 or NT5C2 the expression of RIG-I pathway but of a and results are in line with has been that K48-linked ubiquitination is responsible for protein C. J.M. C.C. and associated with and Res. PubMed Scopus Google Scholar K63-linked ubiquitination is responsible for protein regulation and M. H. of RIG-I by K63-linked PubMed Scopus Google of RIG-I/NF-κB/CCAR1 pathway by TRIM22 and of RIG-I pathway protein and of results in or of TRIM22 and vivo on the tumor from TMZ of of in of and mechanism is used as a protein to the in and we the of TRIM22 and NT5C2 on tumor found that the of TRIM22 and NT5C2 significantly inhibited the of glioma cell proliferation However, or of the in inhibition or of cell proliferation that TRIM22 in the increased expression and of RIG-I, we and cells with an inhibitor of the modification of RIG-I and ubiquitination. found that RIG-I expression increased of treatment with in and treatment the tumor growth inhibition induced by TRIM22 and with to the TMZ treatment the survival of showed a between TRIM22 and that TRIM22 directly as a factor of to expression, but is data that TRIM22 and NT5C2 the RIG-I/NF-κB/CCAR1 TRIM22 expression poor prognosis in patients with the prognosis of patients with of TRIM22 expression, we glioma from patients of of and of and and were on were to for found that the expression of RIG-I, and were in high-grade gliomas than in we the of and and found between and survival of TRIM22 in of of glioma of RIG-I/NF-κB/CCAR1 pathway in and of GBM and of and GBM with TRIM22 of and RIG-I in of glioma of RIG-I, and in and gliomas The survival of patients with TRIM22 expression in treatment and on the survival of patients for and follow-up from of patients with patients with and patients with patients on we follow-up of with had a survival time than with of the same were and expression the as the The results showed that patients with low TRIM22 expression had survival in with the results of the of and RIG-I in and to the between the and to the results and found that the of RIG-I, and were in than that in were in the expression of and the of TRIM22 expression on the of TMZ we the patients and to TRIM22 expression, the patients were a high expression and a low expression found that patients with low TRIM22 expression had survival TMZ treatment data that TRIM22 a of human glioma malignancy and that TMZ has a on patients with low TRIM22 found that TRIM22 in GBM of TRIM22 the proliferation of GBM cells and TMZ sensitivity in a of the of as a NT5C2 in The TRIM22-NT5C2 complex is responsible for the and K48-linked ubiquitination of RIG-I, the Moreover, regulates the expression of tumor is responsible for to the and K. K. M. K. K. of RIG-I and the proliferation of in to between RIG-I and Scholar The of the pathway has been in M. et protein to by with the and signaling 2011; PubMed Scopus Google Wang P.H. M. J.R. and are associated with of and of signaling pathway in Res. PubMed Scopus Google Li H. J.R. of brain is associated with inhibition of PubMed Scopus Google Scholar to while RIG-I to This the of and the for the we found that TRIM22 to a in the of NT5C2 in the that NT5C2 directly to RIG-I on the Moreover, is a of NT5C2 that to TRIM22 and affects RIG-I by the of TRIM22 the of protein NT5C2 as an remains as NT5C2 a role on or with between the is as we have in in vivo this an in or can the use of the same of in the same we and to and However, we found that had on pathway the of TRIM22 expression induced by inhibited the of pathway and the expression of the expression regulation of more than TRIM22 and in the of TRIM22 on the of GBM we that the same treatment had in cells from in the follow-up mechanism we cells with the most results for the This the results of the are or to we It the GBM and cells used are et J. K. Chen A. Li F. Huang Li Wang J. TRIM22 signaling in glioblastoma by the of PubMed Scopus Google Scholar found that the of TRIM22 the of in and with results in The results of the of treatment of GBM in expression of the pathway NT5C2 or TRIM22 of NT5C2 and TRIM22 This by the that K48-linked ubiquitination is responsible for protein K. The regulates PubMed Scopus Google Scholar we that TRIM22 and NT5C2 are responsible for the and K63-linked ubiquitination of RIG-I, the by TRIM22-NT5C2 is to expression The of protein expression that to in protein is to as the of the the RIG-I by the K48-linked ubiquitination responsible for expression than the RIG-I is by K63-linked is responsible for the use of targeted the use of targeted is patients have targeted or in gene expression, of the of the target patients targeted drug therapy to more to the of target to or of the targeted this patients the for targeted drug therapy to between this by in the mechanism of drug more are to is a for the target of of targeted drugs, as as to the for a mechanism of TRIM22 in The of the pathway for multi-target combination therapy for GBM and the benefits of TMZ. the of the of a for more than and and to from the and from were by the and of Moreover, this in with the of the of and and cell were from The and cell were from human glioma cell were and were in The were in a cell and The of cells with TMZ were as TMZ to the and were for used TMZ as a treatment to on glioma cell TRIM22 by and TRIM22 has a on TMZ. were TMZ and TMZ antibody kinase and a RIG-I were from Cell (CCAR1) and were from from and were from The from multiple from for and were from TMZ from and and were cells by The in with the of the The and were and by and were and the cells were in for to the cells with were and by of for and are in of the cell cycle and cell cell cell and were as Wang J. Chen C. Chen W. Wang C. R. glioma and by cell cycle and the Res. PubMed Scopus Google Chen J. W. Chen C. K. Wang C. R. The role of receptor in apoptosis of brain of PubMed Scopus Google Scholar were from cell from the cells were in a for cell and the cells in were to the The cell the cells were with 1 and the cells were for The cell and the cells were with for The to the the used for and 1 to The cells were and the were with a to The cells were and an of the on cells with were for the cells were in a and 1 The cells were on for antibody and for 1 of The were and on a were by for and the The with time the a the and and the in The were used for of the by used to and from to the of the for a following the The expression of the of were the and used as an were and by The used are in and were and by The were cells The cells were for the with the expression of the protein in the cells a factor expression and were and by were and cells a the of the factors and target gene were a and the were to the were in to and in tumor and were to the by the of were from were with and the of the on a the of the the and a in the of the a and 1 to the cells were the brain a The in the for to cell the the with the and the used to tumor time used to TRIM22 expression in tumor and used to TRIM22 expression in GBM and brain from the survival of patients with TRIM22 expression the The used to for The used to between were and used for data The used to the data had a data to the are as the that to a were compared the were of IntroductionGlioma is the most common malignancy of the central nervous system, and patients with high-grade gliomas have a poor prognosis and short survival.1Laws E.R. Parney I.F. Huang W. Anderson F. Morris A.M. Asher A. Lillehei K.O. Bernstein M. Brem H. Sloan A. et al.Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project.J. Neurosurg. 2003; 99: 467-473Crossref PubMed Scopus (547) Google Scholar The use of temozolomide (TMZ) can significantly prolong the survival of patients with high-grade glioma, but drug resistance is increasingly becoming prevalent in patients with this disease.2Lee E.S. Ko K.K. Joe Y.A. Kang S.G. Hong Y.K. Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells.Oncol. Lett. 2011; 2: 115-121Crossref PubMed Scopus (29) Google Scholar,3Xiao-Xing L.I. Wang Z.M. Zuo J.L. Qi-Nian X.U. Wang X.Y. Tao C. Establishment of drug-resistance cell line of human glioma induced by temozolomide and reversion of drug-resistance.Suzhou Univ. J. Med. Sci. 2007; 27: 169-171Google Scholar As cancer treatment has entered the era of targeted molecular therapy,4Yamanaka R. Molecular-targeted therapy for malignant glioma.Brain Nerve. 2009; 61: 177-188PubMed Google Scholar many glioma-associated gene mutations, such as the 19q deletion, have been discovered in recent years.5von Deimling A. Louis D.N. von Ammon K. Petersen I. Wiestler O.D. Seizinger B.R. Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.Cancer Res. 1992; 52: 4277-4279PubMed Google Scholar The targeted therapies currently used for glioma include the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib,6Chang C.Y. Kuan Y.H. Ou Y.C. Li J.R. Wu C.C. Pan P.H. Chen W.Y. Huang H.Y. Chen C.J. Autophagy contributes to gefitinib-induced glioma cell growth inhibition.Exp. Cell Res. 2014; 327: 102-112Crossref PubMed Scopus (35) Google Scholar the vascular endothelial growth factor receptor inhibitor avastin,7Koukourakis G.V. Has bevacizumab (avastin) given extra therapeutic gain in metastatic colorectal cancer and malignant brain gliomas? Systematic review answering this question.Recent Pat. Inflamm. Allergy Drug Discov. 2012; 6: 70-77Crossref PubMed Scopus (8) Google Scholar and the anti-CD20 monoclonal antibody rituximab.8Irani S.R. Gelfand J.M. Bettcher B.M. Singhal N.S. Geschwind M.D. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy.JAMA Neurol. 2014; 71: 896-900Crossref PubMed Scopus (82) Google Scholar It is hoped that therapies targeting multiple signaling pathways or multiple targets in the same signaling pathway are more effective than therapies with single targets. Clinical trials for glioma investigational drugs, such as marimastat in combination with M.D. of temozolomide the in and glioblastoma PubMed Scopus Google Scholar and in combination with and in glioblastoma patients Google Scholar have motif 22 a of the is in a of such as cell F. Chen W. J. Wang H. TRIM22 promotes and of glioblastoma by C.J. a and 2012; PubMed Google Scholar C.J. a and 2012; PubMed Google K. of the gene TRIM22 is of human Res. 2007; PubMed Scopus Google Scholar M. M.D. in human cells to and of high and PubMed Scopus Google Scholar and C. Chen apoptosis is associated with in PubMed Scopus Google Scholar to and W. of TRIM22 as a Res. PubMed Scopus Google Scholar is used as a for targeted therapy in the of many TRIM22 the of cancer through the factor κB (NF-κB) signaling pathway and M. W. K. TRIM22 cancer through the signaling pathway and a J. Google Scholar However, to has revealed the role of TRIM22 in glioma, that TRIM22 signaling in glioblastoma by the of J. K. Chen A. Li F. Huang Li Wang J. TRIM22 signaling in glioblastoma by the of PubMed Scopus Google Scholar The of targeting has from in Chen Wang Li Inhibition of results in and by gene Lett. PubMed Scopus Google Scholar However, with the of by this inhibitor and the of treatment with this inhibitor on multiple is to a targeted drug that can used in combination with However, the pathway plays an role in many is by and can gene has been found that TRIM22 can the the mechanism between TRIM22 and is are the role of TRIM22 in GBM and the protein network mechanism between TRIM22 and for targeted combination therapies for

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