Table1 Studies on the role of alternative autophagy in different diseases

Ulk1-cKO mice

Atg7-cKO mice

Mito-Keima–Tg

Parkin-KO mice

CMs

YFP-Rab9–Tg mice

Rab9-KI mice

Starvation

Glucose deprivation

Hypoxia

Myocardial ischemia

① Mitophagy is induced by energy stress via an Atg7-independent butUlk1-dependent mechanism;

② Ulk1-dependent, but not Atg7-dependent mechanisms protect the heart against ischemic injury;

③ S179 phosphorylation of Rab9 plays an essential role in mediating the assembly of the Ulk1-Rab9-Rip1-Drp1 complex and activating mitophagy in the heart

[3]

DRPLA mice

DN cells

Human fibroblasts

Neuroblastoma cells

Rapamycin

Bafilomycin A1

DRPLA, one of the polyQ diseases

① Canonical autophagy is stalled in DRPLA mice and in human fibroblasts from patients of DRPLA;

② Alternative autopahgy is induced by chronic autophagy blockage in several conditions, including DRPLA and Vici syndrome;

③ The combination of alternative pathways and canonical autophagy blockade, results in dramatic nuclear pathology with disruption of the nuclear organization, bringing about terminal cell atrophy and degeneration

[53]

Ulk1^gt/gt mice

Atg5 ⁻/⁻ mice

Ulk1 ^gt/gt /Atg5⁻/⁻ mice

Erythroblasts

Reticulocytes

Erythroid cells

3-Methyladenine

Rapamycin

Compound C

Staurosporine

Erythrocyte differentiation;

Stress erythropoiesis

① Alternative macroautophagy is responsible for mitochondrial clearance from embryonic reticulocytes,which is Ulk1- dependent and Atg5-independent;

② Ulk1-dependent alternative macroautophagy is also involved in stress erythropoiesis

[86]

TTFs

MEFs

pre-adipocytes

iPSCs

Atg5^−/− TTFs ULK1^−/− TTFs

Rapamycin

AICAR

SMER28 spermidine

3-Methyladenine

Brefeldin A

iPSC reprogramming

① Robust iPSC reprogramming does not rely on canonical autophagy;

② Atg5-independent and Rab9/ULK1-dependent autophagy is

required for reprogramming;

③ The Atg5-independent autophagy induced in reprogramming mediates mitochondrial clearance, by which metabolic switch towards glycolysis is facilitated

[88]

MEFs

hMDMs

J774

3-methyladenine

Bafilomycin A Chloroquine Gentamicin

Francisella tularensis infection

① F. tularensis infection increases autophagic flux;

② Autophagy derived nutrients provide carbon and energy sources that support F. tularensis proliferation;

③ ATG5-independent macroautophagy may be beneficial to

some cytoplasmic bacteria by supplying nutrients to support bacterial growth

[91]

colonic and

intestinal epithelial cell lines

Atg5^−/− or Atg7^−/− MEF cells

Starvation

Chloroquine

LPS

MG132

Crohn’s disease;

bacterial infection

① TRIM31 promotes LPS dependent autophagy in an Atg5- independent alternative process through directly interacting with PE in a palmitoylation-dependent manner;

② TRIM31 induces alternative autophagy, which is essential for eliminating intracellular pathogenic Shigella in intestinal cells;

③ Human cytomegalovirus-infected intestinal cells show a decrease in TRIM31 expression as well as a significant increase in bacterial load, reversible by the introduction of wild-type

TRIM31

[6]