{"id":{"repo_id":"uic","oai_identifier":"oai:figshare.com:article/32995097"},"canonical_url":"https://search.dev.ndltd.org/etd/uic/oai:figshare.com:article/32995097","repository":{"repo_id":"uic","name":"University of Illinois - Chicago","base_url":"https://api.figshare.com/v2/oai"},"display":{"title":"The Role of HOIL 1 Ubiquitin Ligase Activity in MDA5 Antiviral Signaling","abstract":"The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust immune response. RIG-I and MDA5 both signal to MAVS to induce antiviral cytokine induction but respond to different viruses and are activated by distinct mechanisms. The mechanisms regulating RIG-I signaling has been extensively characterized, while considerably less Is known about MDA5 activation and signal transduction. Previous work had identified that the E3 ubiquitin ligase, HOIL1, is essential for the induction of type 1 interferons in response to viral infections primarily sensed by MDA5 but is dispensable for RIG-I mediated interferon induction. However, these findings were confounded by the role of HOIL1 as a critical component of the Linear Ubiquitin Assembly Complex (LUBAC), which consists of another E3 ubiquitin ligase, HOIP, and SHARPIN. The LUBAC has been shown to be a major regulator fo multiple immune-related responses by conjugating linear ubiquitin chains to multiple target proteins, with HOIP functioning as the major catalytic subunit for linear ubiquitination. We have found that HOIL1 E3 ubiquitin ligase activity is required for antiviral signaling driven by activation of MDA5, but not RIG-I. Moreover, HOIL1 ligase activity regulates MDA5 independent of its association with the Linear Ubiquitin Chain Assembly Complex, which promotes both MDA5 and RIG-I signaling in a distinct and more minor capacity. Using a BioID-based proximity-labeling approach, we have identified novel candidate interactors of HOIL1 induced during MDA5 signaling. In addition, we have found that LGP2 is ubiquitinated by HOIL1 during virus infection. Given the central role of LGP2 in MDA5 activation, we propose that HOIL1 regulates MDA5 through ubiquitination of LGP2.","abstract_html":"The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust immune response. RIG-I and MDA5 both signal to MAVS to induce antiviral cytokine induction but respond to different viruses and are activated by distinct mechanisms. The mechanisms regulating RIG-I signaling has been extensively characterized, while considerably less Is known about MDA5 activation and signal transduction. Previous work had identified that the E3 ubiquitin ligase, HOIL1, is essential for the induction of type 1 interferons in response to viral infections primarily sensed by MDA5 but is dispensable for RIG-I mediated interferon induction. However, these findings were confounded by the role of HOIL1 as a critical component of the Linear Ubiquitin Assembly Complex (LUBAC), which consists of another E3 ubiquitin ligase, HOIP, and SHARPIN. The LUBAC has been shown to be a major regulator fo multiple immune-related responses by conjugating linear ubiquitin chains to multiple target proteins, with HOIP functioning as the major catalytic subunit for linear ubiquitination. We have found that HOIL1 E3 ubiquitin ligase activity is required for antiviral signaling driven by activation of MDA5, but not RIG-I. Moreover, HOIL1 ligase activity regulates MDA5 independent of its association with the Linear Ubiquitin Chain Assembly Complex, which promotes both MDA5 and RIG-I signaling in a distinct and more minor capacity. Using a BioID-based proximity-labeling approach, we have identified novel candidate interactors of HOIL1 induced during MDA5 signaling. In addition, we have found that LGP2 is ubiquitinated by HOIL1 during virus infection. Given the central role of LGP2 in MDA5 activation, we propose that HOIL1 regulates MDA5 through ubiquitination of LGP2.","abstract_has_math":false,"creators":["Deion Cheng (24400022)"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026-05-01T00:00:00Z","date_published":"2026-05-01T00:00:00Z","updated_at":"2026-07-27T21:33:48Z","subjects":["Innate Immunology","innate viral sensing"],"languages":[],"rights":["In Copyright","Open Access after 2028-05-01"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.25417/uic.32995097.v1","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Deion Cheng (24400022)"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2026-05-01T00:00:00Z"]},{"key":"dc:relation","label":"Dc Relation","values":["https://figshare.com/articles/thesis/The_Role_of_HOIL_1_Ubiquitin_Ligase_Activity_in_MDA5_Antiviral_Signaling/32995097"]},{"key":"dc:type","label":"Dc Type","values":["Text","Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Innate Immunology","innate viral sensing"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["In Copyright","Open Access after 2028-05-01"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["10.25417/uic.32995097.v1"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust immune response. RIG-I and MDA5 both signal to MAVS to induce antiviral cytokine induction but respond to different viruses and are activated by distinct mechanisms. The mechanisms regulating RIG-I signaling has been extensively characterized, while considerably less Is known about MDA5 activation and signal transduction. Previous work had identified that the E3 ubiquitin ligase, HOIL1, is essential for the induction of type 1 interferons in response to viral infections primarily sensed by MDA5 but is dispensable for RIG-I mediated interferon induction. However, these findings were confounded by the role of HOIL1 as a critical component of the Linear Ubiquitin Assembly Complex (LUBAC), which consists of another E3 ubiquitin ligase, HOIP, and SHARPIN. The LUBAC has been shown to be a major regulator fo multiple immune-related responses by conjugating linear ubiquitin chains to multiple target proteins, with HOIP functioning as the major catalytic subunit for linear ubiquitination. We have found that HOIL1 E3 ubiquitin ligase activity is required for antiviral signaling driven by activation of MDA5, but not RIG-I. Moreover, HOIL1 ligase activity regulates MDA5 independent of its association with the Linear Ubiquitin Chain Assembly Complex, which promotes both MDA5 and RIG-I signaling in a distinct and more minor capacity. Using a BioID-based proximity-labeling approach, we have identified novel candidate interactors of HOIL1 induced during MDA5 signaling. In addition, we have found that LGP2 is ubiquitinated by HOIL1 during virus infection. Given the central role of LGP2 in MDA5 activation, we propose that HOIL1 regulates MDA5 through ubiquitination of LGP2."]},{"key":"dc:title","label":"Title","values":["The Role of HOIL 1 Ubiquitin Ligase Activity in MDA5 Antiviral Signaling"]}]}],"canonical_facts":{"dc:creator":["Deion Cheng (24400022)"],"dc:date":["2026-05-01T00:00:00Z"],"dc:description":["The RIG-I-like receptors (RLRs), RIG-I and MDA5, are innate sensors of RNA virus infections that are critical for mounting a robust immune response. RIG-I and MDA5 both signal to MAVS to induce antiviral cytokine induction but respond to different viruses and are activated by distinct mechanisms. The mechanisms regulating RIG-I signaling has been extensively characterized, while considerably less Is known about MDA5 activation and signal transduction. Previous work had identified that the E3 ubiquitin ligase, HOIL1, is essential for the induction of type 1 interferons in response to viral infections primarily sensed by MDA5 but is dispensable for RIG-I mediated interferon induction. However, these findings were confounded by the role of HOIL1 as a critical component of the Linear Ubiquitin Assembly Complex (LUBAC), which consists of another E3 ubiquitin ligase, HOIP, and SHARPIN. The LUBAC has been shown to be a major regulator fo multiple immune-related responses by conjugating linear ubiquitin chains to multiple target proteins, with HOIP functioning as the major catalytic subunit for linear ubiquitination. We have found that HOIL1 E3 ubiquitin ligase activity is required for antiviral signaling driven by activation of MDA5, but not RIG-I. Moreover, HOIL1 ligase activity regulates MDA5 independent of its association with the Linear Ubiquitin Chain Assembly Complex, which promotes both MDA5 and RIG-I signaling in a distinct and more minor capacity. Using a BioID-based proximity-labeling approach, we have identified novel candidate interactors of HOIL1 induced during MDA5 signaling. In addition, we have found that LGP2 is ubiquitinated by HOIL1 during virus infection. Given the central role of LGP2 in MDA5 activation, we propose that HOIL1 regulates MDA5 through ubiquitination of LGP2."],"dc:identifier":["10.25417/uic.32995097.v1"],"dc:relation":["https://figshare.com/articles/thesis/The_Role_of_HOIL_1_Ubiquitin_Ligase_Activity_in_MDA5_Antiviral_Signaling/32995097"],"dc:rights":["In Copyright","Open Access after 2028-05-01"],"dc:subject":["Innate Immunology","innate viral sensing"],"dc:title":["The Role of HOIL 1 Ubiquitin Ligase Activity in MDA5 Antiviral Signaling"],"dc:type":["Text","Thesis"]},"updated_at":"2026-07-27T21:33:48Z"}