Table 1.
Human tumor viruses, their associated cancers, and mechanisms of autophagy modulation.
| Associated cancer types | Mechanism of interference with autophagy and/or autophagy-regulating pathways |
|---|---|
| Epstein–Barr virus (EBV) Herpesviridae | |
| Burkitt’s and Hodgkin- and non-Hodgkin lymphomas, nasopharyngeal carcinoma, lymphoproliferative diseases | BILF1 ➔ PKR inhibition ➔ may inhibit autophagy [12] |
| LMP1 ➔ JNK activation ➔ may promote autophagy [13,14,15] | |
| LMP1 ➔ NF-κB activation ➔ inhibits autophagy in B cells [16] | |
| LMP1 ➔ p38 activation ➔ may inhibit autophagy [17] | |
| LMP1 ➔ activation of UPR signaling ➔ autophagic markers [18,19] | |
| LMP1/LMP2A ➔ PI3K/mTOR activation ➔ may inhibit autophagy [20,21,22,23,24] | |
| ZTA ➔ NF-κB inhibition ➔ ? [25] | |
| Hepatitis B virus (HBV) Hepadnaviridae | |
| Hepatocellular carcinoma | HBx ➔ increased Beclin-1 transcription ➔ autophagic markers [26] |
| HBx ➔ increased LC3-lipidation and VPS34 activity ➔ incomplete autophagic response [27] | |
| HBx ➔ interacts with p53 ➔ may inhibit autophagy [28] | |
| HBx ➔ p38 activation ➔ may inhibit autophagy [29] | |
| HBx/LHBs/MHBs ➔ ERK activation ➔ may inhibit autophagy [30,31,32] | |
| LHBs ➔ PI3K/AKT/mTOR activation ➔ may inhibit autophagy [32,33,34] | |
| LHBs/MHBs ➔ NF-κB activation ➔ ? [31,35] | |
| SHBs ➔ activation of UPR signaling ➔ incomplete autophagic response [33,36] | |
| SHBs ➔ interacts with LC3 ➔ incomplete autophagic response [36] | |
| Hepatitis C virus (HCV) Flaviviridae | |
| Hepatocellular carcinoma | Core/NS3 ➔ ERK activation ➔ may inhibit autophagy [37,38] |
| Core/NS3 ➔ JNK activation ➔ may promote autophagy [37,38] | |
| Core/NS3/NS4B/NS5A ➔ NF-κB activation ➔ ? [37,39,40] | |
| Core/NS3 ➔ p38 activation ➔ may inhibit autophagy [37,38] | |
| Core/NS3/NS5A ➔ interact with p53 ➔ may inhibit autophagy [41,42,43,44,45] | |
| Core/NS4B ➔ AKT activation ➔ may inhibit autophagy [46] | |
| NS3 ➔ interacts with IRGM ➔ increases autophagic markers [47] | |
| NS4B ➔ activation of UPR signaling ➔ autophagic markers [48] | |
| NS4B ➔ interacts with Rab5 and VPS34 ➔ incomplete autophagic response [48] | |
| NS5A ➔ PI3K/mTOR activation ➔ may inhibit autophagy [49,50] | |
| NS5A ➔ ERK inhibition ➔ may activate autophagy [50,51] | |
| NS5A ➔ PKR inhibition ➔ may inhibit autophagy [52] | |
| NS5A ➔ p38 inhibition ➔ may promote autophagy [53] | |
| NS5B ➔ interacts with ATG5 ➔ ? [54] | |
| ? ➔ increased Beclin-1 expression ➔ autophagic markers [55] | |
| Human papillomavirus, high-risk types (HPV) Papillomaviridae | |
| Cervical, anal and penile cancers, head and neck cancers | E5 ➔ p38 activation ➔ may inhibit autophagy [56] |
| E5/E6/E7 ➔ inhibit XBP1-splicing under basal conditions ➔ ? [57] | |
| E6 ➔ sustained AKT/mTORC1 activity ➔ may inhibit autophagy [58,59] | |
| E6 ➔ inhibits p53 ➔ may inhibit autophagy [60] | |
| E6/E7 ➔ ERK activation ➔ may inhibit autophagy [61] | |
| E7 ➔ AKT activation ➔ may inhibit autophagy [62,63] | |
| E7 ➔ NF-κB inhibition ➔ ? [64,65,66] | |
| E7 ➔ JNK inhibition ➔ may inhibit autophagy [67] | |
| E7 ➔ ? ➔ autophagic markers [68] | |
| Human T-lymphotropic virus (HTLV-1) Retroviridae | |
| Adult T-cell leukemia | Tax ➔ JNK activation ➔ may promote autophagy [69] |
| Tax ➔ sustained AKT/mTORC1 activity ➔ may inhibit autophagy [70,71] | |
| Tax ➔ p38 activation ➔ may inhibit autophagy [69] | |
| Tax ➔ activation of UPR signaling ➔ may promote autophagy [72] | |
| Tax ➔ inhibits p53 ➔ may inhibit autophagy [73] | |
| Tax+HBZ ➔ NF-κB activation ➔ ? [74,75,76,77] | |
| Kaposi’s sarcoma associated herpesvirus (KSHV) Herpesviridae | |
| Kaposi’s sarcoma, pleural effusion lymphoma, multicentric Castleman’s disease | K1 ➔ PI3K/AKT/mTOR activation ➔ may inhibit autophagy [78,79,80] |
| K15 ➔ ERK activation ➔ may inhibit autophagy [81] | |
| K15 ➔ p38 activation ➔ may inhibit autophagy [81] | |
| LANA ➔ inhibits p53 ➔ may inhibit autophagy [82] | |
| ORF45 ➔ sustained ERK/RSK activity ➔ autophagy [83,84] | |
| ORF49 ➔ JNK activation➔ may promote autophagy [85] | |
| ORF49/vGPCR ➔ p38 activation➔ may inhibit autophagy [85,86] | |
| RTA ➔? ➔ increased autophagy [87] | |
| vBCL-2 ➔ interacts with Beclin-1 ➔ autophagy inhibition [88,89] | |
| vFLIP ➔ interacts with ATG3 ➔ autophagy inhibition [90] | |
| vFLIP/K15/ORF75/miR-K1/vGPCR7/vIRF3 ➔ NF-κB activation ➔ ? [81,91,92,93,94,95,96] | |
| vGPCR ➔ PI3Kγ/mTORC1 activation ➔ may inhibit autophagy [97] | |
| vIRF2/vIRF3 ➔ PKR inhibition ➔ may inhibit autophagy [98,99] | |
| vIRF3 ➔ NF-κB inhibition ➔ ? [93,100] | |
| Merkel cell polyomavirus (MCPyV) Polyomaviridae | |
| Merkel cell carcinoma | Small T ➔ mTORC1 activation ➔ may inhibit autophagy [75] |
The table lists established human tumor viruses, their associated malignancies and the autophagy-related proteins and autophagy-regulating signaling pathways they modulate. Note that in many studies, an effect on autophagy has not been explicitly investigated or conclusively and comprehensively validated [101]. With regard to the current literature, it is difficult to predict effects of NF-kB activation on autophagy. ERK, JNK and p38 modulate or have been suggested to modulate autophagy via pathways other than NF-kB, and the predictions listed in this table are based on these mechanisms [102,103,104].