Identification and molecular analysis of RNF31 Q622H germline polymorphism

Oncol Lett. 2022 Sep 21;24(5):394. doi: 10.3892/ol.2022.13514. eCollection 2022 Nov.


The linear ubiquitin chain assembly complex (LUBAC), which is composed of RING finger protein 31 (RNF31), RANBP2-type and C3HC4-type zinc finger containing 1 and SHANK-associated RH domain interactor subunits, is the only ubiquitin ligase to generate Met1-linked linear ubiquitin chains. Linear ubiquitin chains regulate canonical NF-κB activation and cell death. Single nucleotide polymorphisms in RNF31, such as Q584H and Q622L, are known to cause the activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) because of enhanced LUBAC-mediated NF-κB activation. The present study identified a novel Q622H polymorphism of RNF31 in two patients with lung cancer, one of whom had concurrent ABC-DLBCL. Immunohistochemical analyses revealed that although the expression of RNF31 was elevated in both patients, only the ABC-DLBCL specimen showed increased NF-κB activation. Cancer panel analysis showed that the Q622H-related ABC-DLBCL did not harbor co-mutations that were previously reported in Q584H-/Q622L-related ABC-DLBCL. Furthermore, in contrast to Q584H and Q622L, Q622H showed no enhancement effects on LUBAC and NF-κB activity in vitro compared with wild-type RNF31. The present study's structural prediction suggested that the electrostatic interaction related to the Q622 residue may not have had an important role in LUBAC formation. In conclusion, the molecular mechanism and mutational background of RNF31 Q622H differed from that of RNF31 Q584H or Q622L. Furthermore, RNF31 Q622H appeared not to induce NF-κB activation in lung cancer.

Keywords: B-cell lymphoma; NF-κB; RING finger protein 31; linear ubiquitin; lung cancer.

Grants and funding

This work was supported by KAKENHI Grant-in-Aid for Young Scientists B (grant nos. 17K14982 and 17K15038) and KAKENHI Grant-in-Aid for Young Scientists (grant no. 19K18203) Japan Society for the Promotion of Science, Takeda Science Foundation, and YOKOYAMA Foundation for Clinical Pharmacology (grant no. YRY-2006). This work was the result of using research equipment shared in the MEXT Project for promoting the public utilization of advanced research infrastructure, program for supporting the introduction of the new sharing system (grant no. JPMXS0420600120). This work was also supported by the Fostering Health Professionals for Changing Needs of Cancer by MEXT of Japan and Gunma University Initiative for Advanced Research (GIAR).