Reagent or resource	Source	Identifier
Antibodies
Alexa Fluor 488 goat anti-rabbit (1:500)	Invitrogen	Cat# A11034; RRID AB_2576217
Alexa Fluor 546 goat anti-mouse (1:500)	Invitrogen	Cat# A11030; RRID: AB_2534089
Alexa Fluor 594 phalloidin (5 μl)	Invitrogen	Cat# A12381; RRID: AB_2315633
Alexa Fluor 680 donkey anti-goat (1:10,000)	Invitrogen	Cat# A21084; RRID: AB_2535741
Alexa Fluor 680 goat anti-mouse (1:10,000)	Invitrogen	Cat# A21057; RRID: AB_2535723
Alexa Fluor 680 goat anti-rabbit (1:10,000)	Invitrogen	Cat# A21109; RRID: AB_2535758
Alexa Fluor Plus 488 goat anti-rabbit (1:1,000)	Invitrogen	Cat# A32731; RRID: AB_2633280
Alexa Fluor Plus 647 goat anti-mouse (1:1,000)	Invitrogen	Cat# A32728; RRID: AB_2633277
Alexa Fluor Plus 800 goat anti-mouse (1:20,000)	Invitrogen	Cat# A32730; RRID: AB_2633279
goat anti-mouse IgG (H+L)-HRP conjugated (1:1,000)	Bio-Rad	Cat# 170-6516; RRID: AB_11125547
goat anti-rabbit IgG (H+L)-HRP conjugated (1:1,000)	Bio-Rad	Cat# 172-1019; RRID: AB_11125143
IRDye 800CW goat anti-rabbit (1:10,000)	Li-COR	Cat# 926-32211; RRID: AB_621843
goat anti-mouse IgG (H+L)-HRP conjugated (1:5,000)	Thermo Fischer Scientific	Cat# 31430; RRID: AB_228307
goat anti-rabbit IgG (H+L)-HRP conjugated (1:3,000)	Cell Signaling Technology	Cat# 7074; RRID: AB_2099233
goat polyclonal anti-Gal8 (1:400)	R&D Systems	Cat# AF1305; RRID: AB_2137229
rabbit polyclonal anti-C-Gal8 antibody (1:500)	Thermo Fisher Scientific	Cat# PA5-19729; RRID: AB_10984508
rabbit monoclonal anti-GFP (D5.1) (1:1,000)	Cell Signaling Technology	Cat# 2956; RRID: AB_1196615
rabbit monoclonal anti-Gal8 (EPR4857) (1:1,000),	Abcam	Cat# ab109519; RRID: AB_10861755
mouse monoclonal anti-CALCOCO2/NDP52 (1:1,000)	Santa Cruz Biotechnology	Cat# sc-376540, F-6; RRID: AB_11150487
mouse monoclonal anti-FLAG M2 (1:10,000)	Sigma	Cat# F3165; RRID: AB_259529
mouse monoclonal anti-His-tag (1:1,000)	Cedarlanelabs	Cat# CLH101AP
mouse monoclonal anti-IRS2 (1:300)	R&D Systems	Cat# MAB6347, 676415; RRID: AB_10992928
mouse monoclonal anti-PTBP1 (1:500)	Biolegend	Cat# 630101, 3H7; RRID: AB_2171285
mouse monoclonal anti-PTBP1 (1:66)	Biolegend	Cat# 630101, 3H7; RRID: AB_2171285
mouse monoclonal anti-SARS-CoV-2 nucleocapsid (1:1,000)	Invitrogen	Cat# MA5-29981; RRID: AB_2785780
mouse monoclonal anti-β-actin (1:1,000)	Abcam	Cat# ab8226; RRID: AB_306371
mouse monoclonal anti-β-tubulin (1:2,000)	AbLabs	Cat# 21-0018-00, clone BT7R
rabbit anti-CALCOCO2/NDP52 (1:400)	Atlas Antibodies AB	Cat# HPA022989; RRID: AB_1845914
rabbit anti-galectin-8 (1:15)	Atlas Antibodies AB	Cat# HPA030491; RRID: AB_10602345
rabbit anti-goat IgG (H+L)-HRP conjugated (1:1,000)	Bio-Rad	Cat# 172-1034; RRID: AB_11125144
rabbit anti-SARS-CoV-1 3CLpro (1:2000)	Rockland	Cat# 200-401-A51; RRID: AB_828457
rabbit monoclonal anti-FLAG (1:1,000)	Cell Signaling Technology	Cat# 14793S; RRID: AB_2572291
rabbit monoclonal anti-SARS-CoV-2 Spike S1 (1:500)	Sino Biological	Cat# 40150-R007; RRID: AB_2827979
rabbit monoclonal anti-β-actin (1:200)	Abcam	Cat# ab115777; RRID: AB_10899528
rabbit polyclonal anti-CALCOCO2/NDP52 (1:1,000)	Abclonal	Cat# A7358; RRID: AB_2767894
rabbit polyclonal anti-CREB1 (1:1,000)	Abclonal	Cat# A11989; RRID: AB_2758916
rabbit polyclonal anti-FAF1 (1:1,000)	Abclonal	Cat# A2921; RRID: AB_2764739
rabbit polyclonal anti-FYCO1 (1:1,000)	Cusabio	Cat# CSB-PA866262LA01HU; RRID: AB_2892085
rabbit polyclonal anti-KPNA3 (IMA4) (1:1,000)	Abclonal	Cat# A8347; RRID: AB_2770124
rabbit polyclonal anti-MAP4K5 (1:1,000)	Cusabio	Cat# CSB-PA013440DSR2HU; RRID: AB_2892084
rabbit polyclonal anti-NUP107 (1:1,000)	Abclonal	Cat# A13110; RRID: AB_2759959
rabbit polyclonal anti-RPAP1 (1:1,000)	Proteintech	Cat# 15138-1-AP; RRID: AB_2301137
rabbit polyclonal anti-YAP1 (1:1,000)	Abclonal	Cat# A11430; RRID: AB_2758556
Bacterial and virus strains
SARS COV-2/Canada/VIDO-01/2020	Sunnybrook Research Institute, Toronto, ON, Canada	Kindly provided by Dr. S. Mubareka
SARS-CoV-2 (SARS-CoV-2/SB3) clinical isolate	MacMaster University, Hamilton, ON, Canada	(Banerjee et al., 2020)
E. coli BL21(DE3)pLysS	Thermo Fisher Scientific	Cat# C606010
Biological samples
Primary human airway epithelial cells (HAECs) from five donors (1 female, 57; 4 males, 37, 47, 61, 71 years old)	McMaster University, Hamilton, ON, Canada	protocol #HiREB-5099-T)
Normal human lung samples (1 female, 54; 2 males, 15, 45 years old)	Uppsala Biobank	Uppsala Ethical Review Board (Ref # 2002-577, 2005-388).
Human blood from a healthy volunteer	University of British Columbia, BC, Canada	University of British Columbia Human Ethics number: H06-00047
COVID-19 human lung tissue samples (64, 97, 60 and 31 years old)	University Hospital, Huddinge, Stockholm	The Swedish Ethical Review Authority DNR 2020-02446 and 2020-04339.
Chemicals, peptides, and recombinant proteins
14-mer peptides (49) with the sequence AA(X1–X8)YAYR, with X1–X8 being the P4 – P4’ sequence of 46 3CLpro cleavage sites	Genscript	In this paper, Figure 2, Table 1, Figure S2
0.5-ml Amicon Ultra with a 3-kDa cutoff	Millipore-Sigma	Cat#UFC500396
15-ml Amicon Ultra with a 10-kDa cutoff	Millipore-Sigma	Cat#UFC901008
75 μm × 300 mm analytical column filled with ReproSil-Pur C18 (1.8 μm stationary phase)	Dr. Maisch GmbH	https://dr-maisch.com
8-well chamber slide (Lab-Tek II	NalgeNunc	Cat#154534
8-well chambered cover glass	Thermo Fisher Scientific	Cat#155411
Ac-Abu-Tle-Leu-Gln-ACC (quenched fluorescence specific peptide)	N/A	Kindly provided by Dr. Marcin Drag (Rut et al., 2021)
Antibiotic-Antimycotic	GIBCO	Cat#15240062
Benzonase	Sigma	Cat#E1014
bovine serum albumin (BSA)	Sigma	Cat#A7030
calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2/NDP52), GST-tagged recombinant protein (1 – 446 aa, NP_005822.1)	Abnova	Cat#H00010241-P01
Cover Glass Circle #1 12mm	Fisher Scientific	Cat#12-545-80
cyclic AMP-responsive element-binding protein 1 (CREB1), 6x His-tagged recombinant protein (1-327 aa, NM_004379)	Origene	Cat#TP760318
DAPI	Invitrogen	Cat#3571
DMEM (Dulbecco’s Modified Eagle Medium)	Sigma	Cat#D6429
DMEM/F12	GIBCO	Cat#11330057
(MEM) Eagle’s Minimum Essential Medium	Sigma	Cat# M4655-500ML
Empore SPE C18 disc (for StageTips)	VWR	Cat#76333-132
Eosin	Bio-Optica	Cat#05-10003/L
Eppendorf LowBind Protein tubes	Eppendorf	Cat#13-698-794
FBS (Fetal Bovine Serum)	Sigma	Cat#F1051
Fluoroshield with DAPI	Sigma-Aldrich	Cat#F6057
Formaldehyde - “light”	Sigma	Cat#252549
Formaldehyde (20% W/W IN D2O; 13C,99%; D2,98%) - “heavy”	ACP Chemicals	Cat#CDLM4599
Formic acid (MS grade)	Fisher Scientific	Cat#A117-50
galectin-8 (LGALS8) recombinant protein, (1-317 aa, AAF19370.1)	Sino Biological	Cat#10301-HNAE-50
GC376, 3CLpro specific inhibitor	N/A	Kindly provided by Dr. John Vederas (Vuong et al., 2020)
HALT Protease Inhibitor Cocktail	Thermo Fisher Scientific	Cat# PI-78442
HisTrap HP column (Cytiva)	Sigma	Cat#GE17-5247-01
HPG-ALD 100K polymer	UBC Flintbox	www.bit.ly/3iHPs8P
IFN-α2a (carrier free)	PBL Assay Science	Cat#11101-2
IFN-β1a (carrier free)	PBL Assay Science	Cat#11410-2
Imperial protein stain	Thermo Fisher Scientific	Cat#24617
importin subunit alpha-4 (IMA4), partial 6x His-tagged recombinant protein (3-220 aa, NP_002258.2	Aviva System Biology	Cat#OPCD04723
Intercept (PBS) Protein-free Blocking Buffer	Li-COR	Cat#92790001
Lipofectamine 2000	Invitrogen	Cat#11668019
Mayers Htx Plus (Hematoxylin)	Histolab	Cat#01825
MEM-α (Minimum Essential Medium-α)	Thermo Fisher Scientific	Cat#12571063
mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5), GST/6x His-tagged recombinant protein (1- 846 aa, NP_006566.2)	Sino Biological	Cat#11773-H20B-50
MS grade trypsin protease	Thermo Fisher Scientific	Cat#PI90058
N-ethylmaleimide (NEM)	Sigma	Cat#E3876
Native pig myelin basic protein	Abcam	Cat#ab64311
Opti-MEM	Thermo Fisher Scientific	Cat#31985070
Paraformaldehyde (4%)	Sigma	Cat#158127
paraformaldehyde (methanol free)	Thermo Fischer Scientific	Cat#28909
PERTEX mounting medium	Histolab	Cat#00801-Ex
PneumaCult-Ex Plus Media	StemCell Technologies, Inc.	Cat# 05040
polyethylene glycol	Sigma	Cat#P-3265
polypyrimidine-tract binding protein 1 (PTBP1), 6x His-tagged recombinant protein (1-557 aa, NP_002810.1)	Aviva System Biology	Cat#OPCD00681
ProLong Gold antifade mounting media	Invitrogen	Cat#P36930
ProLong™ Glass Antifade Mounting Media	Thermo Fisher Scientific	Cat# P36984
Protease inhibitor cocktail	Bimake.com	Cat#B14002
RIPA buffer	Abcam	Cat#ab156034
RNA polymerase II-associated protein 1 (RPAP1), partial 6x His-tagged recombinant protein (1-351 aa, BC000246)	Proteintech	Cat#AG7856
RPMI-1640	Sigma	Cat#R8758
SARS-CoV-2 Spike S1, 6x His-tagged recombinant protein (16-685 aa, YP_009724390.1)	Sino Biological	Cat#40591-V08H-100
Scepter 60-μm sensor	Millipore-Sigma	Cat# PHCC60500
Sigmafast OPD tablets (peroxidase substrate o-phenylenediamine dihydrochloride)	Sigma	Cat#P9187
Sodium Cyonoborohydrate (NaCNBH3)	Sigma	Cat#156159
thiodigalactoside (TDG) (inhibitor)	Sigma	Cat#SML2310
UltraAb Diluent	Thermo Fisher Scientific	Cat#TA-125-UD
Vacutainer containing sodium citrate	Fisher Scientific	Cat#BD363083
Versene buffer	Thermo Fisher Scientific	Cat#15040066
α-Cyano-4-hydroxycinnamic acid (CHCA MALDI matrix)	Sigma	Cat#2020
β-casein	Sigma	Cat#C6905
Critical commercial assays
Akoya Biosciences Opal 480 reagent pack	Thermo Fisher Scientific	Cat#FP1500001KT
Akoya Biosciences Opal 520 reagent pack	Thermo Fisher Scientific	Cat# FP1487001KT
Akoya Biosciences Opal 570 reagent pack	Thermo Fisher Scientific	Cat# FP1488001KT
Akoya Biosciences Opal 650 reagent pack	Thermo Fisher Scientific	Cat# FP1496001KT
Epridia Lab Vision PT Module Deparaffinization and heat-induced and epitope retrieval Solutions	Thermo Fisher Scientific	Cat#TA-250-PM1X
LookOut Mycoplasma PCR Detection Kit	Sigma	Cat#MP0035
Universal Kinase Activity kit	R&D Systems	Cat#EA004
Deposited data
ProteomeXchange Consortium via the PRIDE partner repository (PXD026797 for HEK293)	ProteomeXchange	http://www.proteomexchange.org/
ProteomeXchange Consortium via the PRIDE partner repository (PXD026815 for BEAS-2B)	ProteomeXchange	https://www.ebi.ac.uk/pride/archive/
Uniport human database (UP000005640_9606)/Byonic	Uniprot	https://www.uniprot.org/
IMEx/IntAct Coronavirus Dataset: SARS-COV-2+human context downloaded from NDEx	NDEx (Perfetto et al., 2020)	http://www.ndexbio.org/#/networkset/4c2268a1-a0f0-11ea-aaef-0ac135e8bacf
(pET21b(+)_SARS-CoV-2_3CLpro-Q306A	Addgene	ID: 177334
pET21b(+)_SARS-CoV-2_3CLpro-C145A-Q306A	Addgene	ID: 177335
Proteomics raw data	Mendeley	https://data.mendeley.com//datasets/b97d5nrb72/1
Protein-protein interaction raw data	Mendeley	https://data.mendeley.com//datasets/b97d5nrb72/1
Uncropped SDS-PAGE gels and western blot images	Mendeley	https://data.mendeley.com/datasets/b97d5nrb72/2
Experimental models: Cell lines
BEAS-2B, human lung bronchus epithelial cells	ATCC	Cat#CRL-9609; RRID: CVCL_0168
Calu-3, human lung adenocarcinoma epithelial cells	ATCC	Cat#HTB-55; RRID: CVCL_0609
HEK293, human embryonic kidney epithelial cells	ATCC	Cat#CRL-1573; RRID: CVCL_0045
Jurkat cells, human immortalized T lymphocytes	ATCC	Cat#TIB-152; RRID: CVCL_0367
HeLa, human cervix adenocarcinoma epithelial cells	ATCC	Cat# CCL-2 RRID: CVCL_0030
Vero E6, monkey kidney epithelial	ATCC	Cat#CRL-1586; RRID: CVCL_0574
Recombinant DNA
pET21b(+)-SARS-CoV-2 3CLpro-Q306A (NC_45512.2)	Genscript	this paper
pET21b(+)-SARS-CoV-2 3CLpro-C145A-Q306A (NC_45512.2)	Genscript	this paper
pcDNA3.1-LGALS8-flag tag (human galectin-8, NM_006499.4)	Genscript	Cat#OHu23472 (ORF clone)
pcDNA3.1-FLAG-tagged-N-LGALS8 (1-158), custom synthesized based on original ORF clone	Genscript	Cat#OHu23472 (ORF clone)
pcDNA3.1-LGALS8 (159-317)-flag tag, custom synthesized based on original ORF clone	Genscript	Cat#OHu23472 (ORF clone)
Software and algorithms
ImageJ 1.53c	(Schneider et al., 2012)	https://imagej.nih.gov/ij/
Prism version 9.0.0. 121	Graphpad	https://www.graphpad.com/
Compass oTOF control 1.9	Bruker	https://www.bruker.com
Byonic PMI-Byonic-Com:v3.8.13	Protein Metrics, San Carlos, CA USA	https://proteinmetrics.com/
Rosetta FlexPepDock (3D molecular docking simulations of peptide-protein and protein-protein docking)	Rosetta	www.rosettacommons.org/software
ProtParam Tool	ExPASy	https://web.expasy.org/protparam/
IntAct app (v 0.9.7) in Cytoscape (v 3.8.2)	Cytoscape	https://cytoscape.org
GLay community clustering algorithm plugin clusterMaker2 (v 1.3.1) in Cytoscape (v 3.8.2)	Cytoscape	https://cytoscape.org
Scaffold (v4.11.0)	Proteome Software Inc., Portland, OR, USA	http://www.proteomesoftware.com
Skyline (v 20.1.0.155)	MacCoss Lab, UW, Seattle, WA, USA	https://skyline.ms
TopFinder (part of TopFind 4.1)	Overall Lab, UBC, Vancouver, BC, Canada	https://topfind.clip.msl.ubc.ca
Data Explorer (v 4.5) for 4700 spectra analysis	Applied Biosystem
GelAnalyzer version 19.1.	Istvan Lazar Jr., Ph.D. and Istvan Lazar Sr., Ph.D., C.Sc	www.gelanalyzer.com
Image Studio Software version 5.2.5.	Li-Cor	www.licor.com
iceLogos	Colaert, N. et al. Nature Methods 6, 786-787 (2009)	https://iomics.ugent.be/icelogoserver/
Other
Zeiss LSM 880 Inverted Confocal Microscope	Zeiss	www.zeiss.com
Leica TCS SP5 II Confocal Microscope	Leica	www.leica-microsystems.com
Zeiss Axio Scan.Z1 Slide Scanner equipped with a Zeiss Colibri 7, Type RGB-UV fluorescence light source	Zeiss	www.zeiss.com
POLARstar optima microplate reader	BMG LABTECH	discontinued
Aperio AT2 slide scanner	Leica	www.leica-microsystems.com
TMArrayer	Pathology Devices	https://pathologydevices.com
Beecher Instruments Manual Tissue Arrayer MTA-1	Estigen OÜ	https://estigen.com/
Waterfall Microm HM 355S	Thermo Fisher Scientific	www.thermofisher.com
Decloaking chamber	Biocare Medical	https://biocare.net
Odyssey-Classic infrared imager (application software 3.0.30)	Li-COR	https://www.licor.com
SpectraMax 384 Plus spectrophotometer plate reader	Molecular Devices	www.moleculardevices.com
Sonic Dismembrator Model 100	Fisher Scientific	www.fishersci.ca
Scepter handheld automated cell counter	Millipore-Sigma	discontinued
Leica DMRA2 microscope	Leica	www.leica-microsystems.com
ӒKTAexplorer	Amersham Pharmacia Biotech, now Cytiva	discontinued
Easy nLC-1000 (UHPLC) coupled to Impact II	Thermo-Fisher Scientific	www.thermofisher.com
Impact II Q-TOF mass spectrometer with a CaptiveSpray ionization interface equipped with a NanoBooster	Bruker-Daltonics	www.bruker.com
MALDI-TOF/TOF 4700 Proteomics Analyzer	Applied Biosystems	discontinued
ABI 494 Protein Sequencer	Applied Biosystems	discontinued